When provided at the bedside of patients hospitalized for heart failure, an electronic health record (EHR) alert with prognostic information did not improve outcomes or appear to have any impact on what treatments were offered.

There was no signal that the EHR prognostic alerts, which identified the 12-month risk of mortality, had any impact on any of a variety of clinical-decision-making metrics or on any of the primary or secondary outcomes, according to Tariq Ahmad, MD, who reported results of the randomized REVEAL-HF trial, presented at the American Heart Association scientific sessions.

“These results call into question the hypothesis that accurate prognostic information alone will lead to better clinical decision-making,” said Dr. Ahmad, medical director of the Heart Transplant and Mechanical Circulatory Support Program at Yale University, New Haven, Conn., and principal investigator of REVEAL-HF.

He acknowledged that the possibility that many clinicians pay little or no attention to EHR alert might have played a role in the negative results.

At four participating Yale-affiliated clinical centers, all patients hospitalized for acute heart failure were randomized as long as they were over the age of 18, had an N-terminal pro-brain natriuretic peptide (NT-proBNP) level above 500 pg/mL, and had been placed on IV diuretics within 24 hours of admission. In the experimental arm, the provider at the time of entering orders received an EHR alert with an estimate of the risk of all-cause mortality at 12 months. There was no such alert for patients managed in the control arm.
 

Twelve-month mortality estimates calculated

The all-cause mortality risk was calculated on a sizeable list of variables that included laboratory results, such as cell counts, and patient characteristics, such as weight and age. The risk estimate was displayed along with a five-category color-coded bar to provide context for the risk in the spectrum of very low, low, medium, high, and very high likelihood of death within 12 months.

The 1,590 patients randomized to the experimental arm and the 1,534 patients randomized to the usual care arm did not differ significantly in any baseline characteristics. The median age was about 77 years, the mean left ventricular ejection fraction (LVEF) was 55%. About 29% had an LVEF below 40%, about 40% had chronic kidney disease, and about 30% had chronic obstructive pulmonary disease (COPD).

The composite primary outcome of all-cause mortality or rehospitalization within 12 months was reached by 38.9% and 39.3% (P = 0.82) of the intervention and control arms, respectively. The components of the primary outcome were also nearly identical, as was inpatient mortality (8.4% vs. 8.8%; P = 0.72).

There were no significant differences in any of the secondary outcomes, which included rates of 30-day rehospitalizations, discharge on guideline-recommended heart failure therapies, implantation of a cardioverter defibrillator, use of a left ventricular assist device, or heart transplant.

The proportion of patients referred for palliative care was almost identical in the very low, low, and medium risk groups. In the high (23.4 vs. 15.6; P = 0.19) and very high (50% vs. 40%; P = 0.92) groups, there were numerically more referrals in the group randomized to usual care, but these rates did not reach significance.
 

No differences seen in discharge meds

There was essentially no difference between groups in the rates at which patients were discharged on beta-blockers, renin-angiotensin system inhibitors, sodium-glucose co-transporter type 2 (SGLT2) inhibitors, or mineralocorticoid antagonists.

When prespecified subgroups, such as those older than age 75 years relative to those younger, males relative to females, Black versus White participants, patients with reduced ejection fraction (HFrEF) relative to preserved ejection fraction (HFpEF), and intensive care unit versus non-ICU patients, were compared, there were no indications that the EHR alert improved outcomes.

Invited discussant Harriette G. C. Van Spall, MD, director of digital health and virtual care and associate professor of cardiology at McMaster University, Hamilton, Ont., did not dispute the conclusions, but she pointed out several potential explanations for the neutral result.

Not least, nearly 75% of those enrolled had low risk or very low risk for adverse outcomes within 1 year, so the opportunity to show a reduction in events, including all-cause mortality, was limited.

“This was largely a HFpEF population, for which there are no treatments for which a risk score would change therapy,” she said.
 

EHR alert efficacy questioned

There is considerable evidence that risk prediction tools “are common but underutilized in HF,” Dr. Van Spall added. She noted that many clinicians find alerts in the EHR more annoying than informative, and it remains unknown what proportion of clinicians pay attention to them, particularly in the absence of evidence that they lead to meaningful improvements in care over their own clinical judgment.

Dr. Ahmad agreed.

“I think that we need to study these alerts in a clinical trial format,” he said. Acknowledging that alerts have been poorly received by many clinicians, Dr. Ahmad said that trials to validate the impact of any specific alert are needed to improve their credibility. If a positive impact cannot be shown, he said the alert should be eliminated, leaving only the alerts with proven clinical value.

Dr. Ahmad reported financial relationships with Amgen, AstraZeneca, Boehringer Ingelheim, Cytokinetics, Novartis, and Relypsa. Dr. Van Spall reports no potential conflicts of interest.

When provided at the bedside of patients hospitalized for heart failure, an electronic health record (EHR) alert with prognostic information did not improve outcomes or appear to have any impact on what treatments were offered.

There was no signal that the EHR prognostic alerts, which identified the 12-month risk of mortality, had any impact on any of a variety of clinical-decision-making metrics or on any of the primary or secondary outcomes, according to Tariq Ahmad, MD, who reported results of the randomized REVEAL-HF trial, presented at the American Heart Association scientific sessions.

“These results call into question the hypothesis that accurate prognostic information alone will lead to better clinical decision-making,” said Dr. Ahmad, medical director of the Heart Transplant and Mechanical Circulatory Support Program at Yale University, New Haven, Conn., and principal investigator of REVEAL-HF.

He acknowledged that the possibility that many clinicians pay little or no attention to EHR alert might have played a role in the negative results.

At four participating Yale-affiliated clinical centers, all patients hospitalized for acute heart failure were randomized as long as they were over the age of 18, had an N-terminal pro-brain natriuretic peptide (NT-proBNP) level above 500 pg/mL, and had been placed on IV diuretics within 24 hours of admission. In the experimental arm, the provider at the time of entering orders received an EHR alert with an estimate of the risk of all-cause mortality at 12 months. There was no such alert for patients managed in the control arm.
 

Twelve-month mortality estimates calculated

The all-cause mortality risk was calculated on a sizeable list of variables that included laboratory results, such as cell counts, and patient characteristics, such as weight and age. The risk estimate was displayed along with a five-category color-coded bar to provide context for the risk in the spectrum of very low, low, medium, high, and very high likelihood of death within 12 months.

The 1,590 patients randomized to the experimental arm and the 1,534 patients randomized to the usual care arm did not differ significantly in any baseline characteristics. The median age was about 77 years, the mean left ventricular ejection fraction (LVEF) was 55%. About 29% had an LVEF below 40%, about 40% had chronic kidney disease, and about 30% had chronic obstructive pulmonary disease (COPD).

The composite primary outcome of all-cause mortality or rehospitalization within 12 months was reached by 38.9% and 39.3% (P = 0.82) of the intervention and control arms, respectively. The components of the primary outcome were also nearly identical, as was inpatient mortality (8.4% vs. 8.8%; P = 0.72).

There were no significant differences in any of the secondary outcomes, which included rates of 30-day rehospitalizations, discharge on guideline-recommended heart failure therapies, implantation of a cardioverter defibrillator, use of a left ventricular assist device, or heart transplant.

The proportion of patients referred for palliative care was almost identical in the very low, low, and medium risk groups. In the high (23.4 vs. 15.6; P = 0.19) and very high (50% vs. 40%; P = 0.92) groups, there were numerically more referrals in the group randomized to usual care, but these rates did not reach significance.
 

No differences seen in discharge meds

There was essentially no difference between groups in the rates at which patients were discharged on beta-blockers, renin-angiotensin system inhibitors, sodium-glucose co-transporter type 2 (SGLT2) inhibitors, or mineralocorticoid antagonists.

When prespecified subgroups, such as those older than age 75 years relative to those younger, males relative to females, Black versus White participants, patients with reduced ejection fraction (HFrEF) relative to preserved ejection fraction (HFpEF), and intensive care unit versus non-ICU patients, were compared, there were no indications that the EHR alert improved outcomes.

Invited discussant Harriette G. C. Van Spall, MD, director of digital health and virtual care and associate professor of cardiology at McMaster University, Hamilton, Ont., did not dispute the conclusions, but she pointed out several potential explanations for the neutral result.

Not least, nearly 75% of those enrolled had low risk or very low risk for adverse outcomes within 1 year, so the opportunity to show a reduction in events, including all-cause mortality, was limited.

“This was largely a HFpEF population, for which there are no treatments for which a risk score would change therapy,” she said.
 

EHR alert efficacy questioned

There is considerable evidence that risk prediction tools “are common but underutilized in HF,” Dr. Van Spall added. She noted that many clinicians find alerts in the EHR more annoying than informative, and it remains unknown what proportion of clinicians pay attention to them, particularly in the absence of evidence that they lead to meaningful improvements in care over their own clinical judgment.

Dr. Ahmad agreed.

“I think that we need to study these alerts in a clinical trial format,” he said. Acknowledging that alerts have been poorly received by many clinicians, Dr. Ahmad said that trials to validate the impact of any specific alert are needed to improve their credibility. If a positive impact cannot be shown, he said the alert should be eliminated, leaving only the alerts with proven clinical value.

Dr. Ahmad reported financial relationships with Amgen, AstraZeneca, Boehringer Ingelheim, Cytokinetics, Novartis, and Relypsa. Dr. Van Spall reports no potential conflicts of interest.

When provided at the bedside of patients hospitalized for heart failure, an electronic health record (EHR) alert with prognostic information did not improve outcomes or appear to have any impact on what treatments were offered.

There was no signal that the EHR prognostic alerts, which identified the 12-month risk of mortality, had any impact on any of a variety of clinical-decision-making metrics or on any of the primary or secondary outcomes, according to Tariq Ahmad, MD, who reported results of the randomized REVEAL-HF trial, presented at the American Heart Association scientific sessions.

“These results call into question the hypothesis that accurate prognostic information alone will lead to better clinical decision-making,” said Dr. Ahmad, medical director of the Heart Transplant and Mechanical Circulatory Support Program at Yale University, New Haven, Conn., and principal investigator of REVEAL-HF.

He acknowledged that the possibility that many clinicians pay little or no attention to EHR alert might have played a role in the negative results.

At four participating Yale-affiliated clinical centers, all patients hospitalized for acute heart failure were randomized as long as they were over the age of 18, had an N-terminal pro-brain natriuretic peptide (NT-proBNP) level above 500 pg/mL, and had been placed on IV diuretics within 24 hours of admission. In the experimental arm, the provider at the time of entering orders received an EHR alert with an estimate of the risk of all-cause mortality at 12 months. There was no such alert for patients managed in the control arm.
 

Twelve-month mortality estimates calculated

The all-cause mortality risk was calculated on a sizeable list of variables that included laboratory results, such as cell counts, and patient characteristics, such as weight and age. The risk estimate was displayed along with a five-category color-coded bar to provide context for the risk in the spectrum of very low, low, medium, high, and very high likelihood of death within 12 months.

The 1,590 patients randomized to the experimental arm and the 1,534 patients randomized to the usual care arm did not differ significantly in any baseline characteristics. The median age was about 77 years, the mean left ventricular ejection fraction (LVEF) was 55%. About 29% had an LVEF below 40%, about 40% had chronic kidney disease, and about 30% had chronic obstructive pulmonary disease (COPD).

The composite primary outcome of all-cause mortality or rehospitalization within 12 months was reached by 38.9% and 39.3% (P = 0.82) of the intervention and control arms, respectively. The components of the primary outcome were also nearly identical, as was inpatient mortality (8.4% vs. 8.8%; P = 0.72).

There were no significant differences in any of the secondary outcomes, which included rates of 30-day rehospitalizations, discharge on guideline-recommended heart failure therapies, implantation of a cardioverter defibrillator, use of a left ventricular assist device, or heart transplant.

The proportion of patients referred for palliative care was almost identical in the very low, low, and medium risk groups. In the high (23.4 vs. 15.6; P = 0.19) and very high (50% vs. 40%; P = 0.92) groups, there were numerically more referrals in the group randomized to usual care, but these rates did not reach significance.
 

No differences seen in discharge meds

There was essentially no difference between groups in the rates at which patients were discharged on beta-blockers, renin-angiotensin system inhibitors, sodium-glucose co-transporter type 2 (SGLT2) inhibitors, or mineralocorticoid antagonists.

When prespecified subgroups, such as those older than age 75 years relative to those younger, males relative to females, Black versus White participants, patients with reduced ejection fraction (HFrEF) relative to preserved ejection fraction (HFpEF), and intensive care unit versus non-ICU patients, were compared, there were no indications that the EHR alert improved outcomes.

Invited discussant Harriette G. C. Van Spall, MD, director of digital health and virtual care and associate professor of cardiology at McMaster University, Hamilton, Ont., did not dispute the conclusions, but she pointed out several potential explanations for the neutral result.

Not least, nearly 75% of those enrolled had low risk or very low risk for adverse outcomes within 1 year, so the opportunity to show a reduction in events, including all-cause mortality, was limited.

“This was largely a HFpEF population, for which there are no treatments for which a risk score would change therapy,” she said.
 

EHR alert efficacy questioned

There is considerable evidence that risk prediction tools “are common but underutilized in HF,” Dr. Van Spall added. She noted that many clinicians find alerts in the EHR more annoying than informative, and it remains unknown what proportion of clinicians pay attention to them, particularly in the absence of evidence that they lead to meaningful improvements in care over their own clinical judgment.

Dr. Ahmad agreed.

“I think that we need to study these alerts in a clinical trial format,” he said. Acknowledging that alerts have been poorly received by many clinicians, Dr. Ahmad said that trials to validate the impact of any specific alert are needed to improve their credibility. If a positive impact cannot be shown, he said the alert should be eliminated, leaving only the alerts with proven clinical value.

Dr. Ahmad reported financial relationships with Amgen, AstraZeneca, Boehringer Ingelheim, Cytokinetics, Novartis, and Relypsa. Dr. Van Spall reports no potential conflicts of interest.

Induction therapy with Janus kinase inhibitor upadacitinib is superior to placebo for patients with moderately to severely active ulcerative colitis (UC), regardless of prior biologic treatments, based on results of the phase 3 U-ACHIEVE trial.

Clinical responses in the upadacitinib group occurred as soon as 2 weeks and were sustained through the 8-week study period, reported lead author Silvio Danese, MD, PhD, of Humanitas Clinical and Research Center IRCCS and Hunimed, Milan.

“Despite availability of multiple treatment options, many patients with ulcerative colitis do not achieve disease remission with current therapies and unmet therapeutic need remains, especially in patients with moderate to severe disease,” said coauthor Peter Higgins, MD, PhD, of the University of Michigan, Ann Arbor, who presented findings at the annual meeting of the American College of Gastroenterology.

The U-ACHIEVE trial involved 474 patients with moderate to severe UC randomized to receive either upadacitinib induction therapy (45 mg once daily; n = 319) or placebo (n = 155). The primary endpoint was clinical remission at week 8. Secondary endpoints included endoscopic improvement at week 8, endoscopic remission at week 8, clinical response at week 8, clinical response at week 2, histologic-endoscopic mucosal improvement at week 8, and adverse events.

The study population was “very sick” and “very experienced,” Dr. Higgins said, noting that approximately half of the patients had inadequate responses to prior biologics, and within this subgroup of inadequate responders, approximately two-thirds of the patients had received more than one prior biologic. According to Dr. Higgins, this helps explain why 12.3% of the patients in the placebo group discontinued therapy, compared with just 3.8% in the upadacitinib group – because most patients involved were “quite ill.”

At week 8, 26.1% of the patients in the upadacitinib group had achieved clinical remission, versus 4.8% of the patients given placebo (26.1% vs. 4.8%; P < .0001). Clinical response at week 2 followed a similar pattern (60.1% vs. 27.3%; P < .001), as did clinical response at week 8 (72.6% vs. 27.3%; P < .0001).

All other 8-week secondary endpoints also significantly favored upadacitinib, including endoscopic improvement (36.3% vs 7.4%), endoscopic remission (13.7% vs 1.3%), and histologic-endoscopic mucosal improvement (29.9% vs. 6.5%).

Serious and severe adverse events were more common in the placebo group, and patients in the placebo group more frequently discontinued therapy because of treatment-related adverse events. While rates of serious infection were similar between groups, patients taking upadacitinib had higher rates of neutropenia and lymphopenia.

Based on these findings, the investigators concluded that upadacitinib induction therapy is superior to placebo for clinical remission and clinical response regardless of previous treatment failure.

According to Jordan E. Axelrad, MD, of New York University Langone Health, the findings reflect a real-world setting and clinicians should take note of the rapid response observed with upadacitinib.

“This was a relatively sick group, so you know this reflects what we’re seeing in clinical practice,” Dr. Axelrad said in an interview. “Clinical response was detected as early week 2, and that’s extremely important to highlight, because a lot of our drugs that we have on the market – some of these biologics – may take a little time to work. Having a drug that can work fast and is effective is critical.”

Dr. Axelrad suggested that second-line JAK inhibitors like upadacitinib, which target JAK proteins more selectively than first-generation agents, may alleviate some lingering concerns about JAK inhibitor safety; still, optimal treatment sequencing remains unclear.

“With more selective inhibition, you’re getting less of that side-effect profile,” Dr. Axelrad said, noting that long-term data is needed to confirm this likelihood. “The real question moving forward is: Will upadacitinib replace first-generation JAK inhibitors as a category, or, because of the broader safety profile, will it come earlier in the positioning of where we put our drugs for colitis?”

Dr. Axelrad suggested that the answer may ultimately come from regulators, although patients could also guide decision-making.

“Oral drugs are a really important mode of administration that we’re missing for the moderate to severe group,” he said. “Should [further clinical trials] demonstrate superior safety to nonselective JAK inhibitors, upadacitinib could be a first-line option for patients who don’t want to be taking an infusion or injection, more especially so for those that are already biologically experienced, or need something fast.”

Siddharth Singh, MD, director of the IBD Center at the University of California, San Diego, called U-ACHIEVE a “pivotal trial” that demonstrated the “remarkable efficacy” of upadacitinib for moderate to severe ulcerative colitis; still, he noted that drug sequencing remains undetermined.

“It’s unclear whether or not it’ll be the best in class for JAK inhibitors right now,” Dr. Singh said in an interview. “A lot of that hinges on the safety of this drug. In terms of positioning, it depends on whether the [Food and Drug Administration] requires patients to have failed anti–[tumor necrosis factor] therapy before using this drug, like tofacitinib.”

That may depend on long-term data, he suggested.

“Right now, it is hard to comment on the relative safety of upadacitinib versus tofacitinib,” Dr. Singh said. “While the JAK1 selectivity may contribute to efficacy by allowing us to use a higher dose, it’s unclear whether the higher dose of this medication is any safer than tofacitinib. Longer term, 5- to 7-year registry studies of real-world data are warranted to examine risk of cardiovascular disease, thromboembolism, malignancy, and mortality with upadacitinib.

“How to sequence and position these therapies in real-world practice is a key question,” he concluded.

The study was supported by AbbVie. The investigators disclosed additional affiliations with Genentech, Ferring, AstraZeneca, and others. Dr. Axelrad has previously consulted for AbbVie. Dr. Singh has received research funding from AbbVie, Pfizer, and Janssen in the last 24 months, as well as personal fees from Pfizer for an ad hoc grant review.

Induction therapy with Janus kinase inhibitor upadacitinib is superior to placebo for patients with moderately to severely active ulcerative colitis (UC), regardless of prior biologic treatments, based on results of the phase 3 U-ACHIEVE trial.

Clinical responses in the upadacitinib group occurred as soon as 2 weeks and were sustained through the 8-week study period, reported lead author Silvio Danese, MD, PhD, of Humanitas Clinical and Research Center IRCCS and Hunimed, Milan.

“Despite availability of multiple treatment options, many patients with ulcerative colitis do not achieve disease remission with current therapies and unmet therapeutic need remains, especially in patients with moderate to severe disease,” said coauthor Peter Higgins, MD, PhD, of the University of Michigan, Ann Arbor, who presented findings at the annual meeting of the American College of Gastroenterology.

The U-ACHIEVE trial involved 474 patients with moderate to severe UC randomized to receive either upadacitinib induction therapy (45 mg once daily; n = 319) or placebo (n = 155). The primary endpoint was clinical remission at week 8. Secondary endpoints included endoscopic improvement at week 8, endoscopic remission at week 8, clinical response at week 8, clinical response at week 2, histologic-endoscopic mucosal improvement at week 8, and adverse events.

The study population was “very sick” and “very experienced,” Dr. Higgins said, noting that approximately half of the patients had inadequate responses to prior biologics, and within this subgroup of inadequate responders, approximately two-thirds of the patients had received more than one prior biologic. According to Dr. Higgins, this helps explain why 12.3% of the patients in the placebo group discontinued therapy, compared with just 3.8% in the upadacitinib group – because most patients involved were “quite ill.”

At week 8, 26.1% of the patients in the upadacitinib group had achieved clinical remission, versus 4.8% of the patients given placebo (26.1% vs. 4.8%; P < .0001). Clinical response at week 2 followed a similar pattern (60.1% vs. 27.3%; P < .001), as did clinical response at week 8 (72.6% vs. 27.3%; P < .0001).

All other 8-week secondary endpoints also significantly favored upadacitinib, including endoscopic improvement (36.3% vs 7.4%), endoscopic remission (13.7% vs 1.3%), and histologic-endoscopic mucosal improvement (29.9% vs. 6.5%).

Serious and severe adverse events were more common in the placebo group, and patients in the placebo group more frequently discontinued therapy because of treatment-related adverse events. While rates of serious infection were similar between groups, patients taking upadacitinib had higher rates of neutropenia and lymphopenia.

Based on these findings, the investigators concluded that upadacitinib induction therapy is superior to placebo for clinical remission and clinical response regardless of previous treatment failure.

According to Jordan E. Axelrad, MD, of New York University Langone Health, the findings reflect a real-world setting and clinicians should take note of the rapid response observed with upadacitinib.

“This was a relatively sick group, so you know this reflects what we’re seeing in clinical practice,” Dr. Axelrad said in an interview. “Clinical response was detected as early week 2, and that’s extremely important to highlight, because a lot of our drugs that we have on the market – some of these biologics – may take a little time to work. Having a drug that can work fast and is effective is critical.”

Dr. Axelrad suggested that second-line JAK inhibitors like upadacitinib, which target JAK proteins more selectively than first-generation agents, may alleviate some lingering concerns about JAK inhibitor safety; still, optimal treatment sequencing remains unclear.

“With more selective inhibition, you’re getting less of that side-effect profile,” Dr. Axelrad said, noting that long-term data is needed to confirm this likelihood. “The real question moving forward is: Will upadacitinib replace first-generation JAK inhibitors as a category, or, because of the broader safety profile, will it come earlier in the positioning of where we put our drugs for colitis?”

Dr. Axelrad suggested that the answer may ultimately come from regulators, although patients could also guide decision-making.

“Oral drugs are a really important mode of administration that we’re missing for the moderate to severe group,” he said. “Should [further clinical trials] demonstrate superior safety to nonselective JAK inhibitors, upadacitinib could be a first-line option for patients who don’t want to be taking an infusion or injection, more especially so for those that are already biologically experienced, or need something fast.”

Siddharth Singh, MD, director of the IBD Center at the University of California, San Diego, called U-ACHIEVE a “pivotal trial” that demonstrated the “remarkable efficacy” of upadacitinib for moderate to severe ulcerative colitis; still, he noted that drug sequencing remains undetermined.

“It’s unclear whether or not it’ll be the best in class for JAK inhibitors right now,” Dr. Singh said in an interview. “A lot of that hinges on the safety of this drug. In terms of positioning, it depends on whether the [Food and Drug Administration] requires patients to have failed anti–[tumor necrosis factor] therapy before using this drug, like tofacitinib.”

That may depend on long-term data, he suggested.

“Right now, it is hard to comment on the relative safety of upadacitinib versus tofacitinib,” Dr. Singh said. “While the JAK1 selectivity may contribute to efficacy by allowing us to use a higher dose, it’s unclear whether the higher dose of this medication is any safer than tofacitinib. Longer term, 5- to 7-year registry studies of real-world data are warranted to examine risk of cardiovascular disease, thromboembolism, malignancy, and mortality with upadacitinib.

“How to sequence and position these therapies in real-world practice is a key question,” he concluded.

The study was supported by AbbVie. The investigators disclosed additional affiliations with Genentech, Ferring, AstraZeneca, and others. Dr. Axelrad has previously consulted for AbbVie. Dr. Singh has received research funding from AbbVie, Pfizer, and Janssen in the last 24 months, as well as personal fees from Pfizer for an ad hoc grant review.

Induction therapy with Janus kinase inhibitor upadacitinib is superior to placebo for patients with moderately to severely active ulcerative colitis (UC), regardless of prior biologic treatments, based on results of the phase 3 U-ACHIEVE trial.

Clinical responses in the upadacitinib group occurred as soon as 2 weeks and were sustained through the 8-week study period, reported lead author Silvio Danese, MD, PhD, of Humanitas Clinical and Research Center IRCCS and Hunimed, Milan.

“Despite availability of multiple treatment options, many patients with ulcerative colitis do not achieve disease remission with current therapies and unmet therapeutic need remains, especially in patients with moderate to severe disease,” said coauthor Peter Higgins, MD, PhD, of the University of Michigan, Ann Arbor, who presented findings at the annual meeting of the American College of Gastroenterology.

The U-ACHIEVE trial involved 474 patients with moderate to severe UC randomized to receive either upadacitinib induction therapy (45 mg once daily; n = 319) or placebo (n = 155). The primary endpoint was clinical remission at week 8. Secondary endpoints included endoscopic improvement at week 8, endoscopic remission at week 8, clinical response at week 8, clinical response at week 2, histologic-endoscopic mucosal improvement at week 8, and adverse events.

The study population was “very sick” and “very experienced,” Dr. Higgins said, noting that approximately half of the patients had inadequate responses to prior biologics, and within this subgroup of inadequate responders, approximately two-thirds of the patients had received more than one prior biologic. According to Dr. Higgins, this helps explain why 12.3% of the patients in the placebo group discontinued therapy, compared with just 3.8% in the upadacitinib group – because most patients involved were “quite ill.”

At week 8, 26.1% of the patients in the upadacitinib group had achieved clinical remission, versus 4.8% of the patients given placebo (26.1% vs. 4.8%; P < .0001). Clinical response at week 2 followed a similar pattern (60.1% vs. 27.3%; P < .001), as did clinical response at week 8 (72.6% vs. 27.3%; P < .0001).

All other 8-week secondary endpoints also significantly favored upadacitinib, including endoscopic improvement (36.3% vs 7.4%), endoscopic remission (13.7% vs 1.3%), and histologic-endoscopic mucosal improvement (29.9% vs. 6.5%).

Serious and severe adverse events were more common in the placebo group, and patients in the placebo group more frequently discontinued therapy because of treatment-related adverse events. While rates of serious infection were similar between groups, patients taking upadacitinib had higher rates of neutropenia and lymphopenia.

Based on these findings, the investigators concluded that upadacitinib induction therapy is superior to placebo for clinical remission and clinical response regardless of previous treatment failure.

According to Jordan E. Axelrad, MD, of New York University Langone Health, the findings reflect a real-world setting and clinicians should take note of the rapid response observed with upadacitinib.

“This was a relatively sick group, so you know this reflects what we’re seeing in clinical practice,” Dr. Axelrad said in an interview. “Clinical response was detected as early week 2, and that’s extremely important to highlight, because a lot of our drugs that we have on the market – some of these biologics – may take a little time to work. Having a drug that can work fast and is effective is critical.”

Dr. Axelrad suggested that second-line JAK inhibitors like upadacitinib, which target JAK proteins more selectively than first-generation agents, may alleviate some lingering concerns about JAK inhibitor safety; still, optimal treatment sequencing remains unclear.

“With more selective inhibition, you’re getting less of that side-effect profile,” Dr. Axelrad said, noting that long-term data is needed to confirm this likelihood. “The real question moving forward is: Will upadacitinib replace first-generation JAK inhibitors as a category, or, because of the broader safety profile, will it come earlier in the positioning of where we put our drugs for colitis?”

Dr. Axelrad suggested that the answer may ultimately come from regulators, although patients could also guide decision-making.

“Oral drugs are a really important mode of administration that we’re missing for the moderate to severe group,” he said. “Should [further clinical trials] demonstrate superior safety to nonselective JAK inhibitors, upadacitinib could be a first-line option for patients who don’t want to be taking an infusion or injection, more especially so for those that are already biologically experienced, or need something fast.”

Siddharth Singh, MD, director of the IBD Center at the University of California, San Diego, called U-ACHIEVE a “pivotal trial” that demonstrated the “remarkable efficacy” of upadacitinib for moderate to severe ulcerative colitis; still, he noted that drug sequencing remains undetermined.

“It’s unclear whether or not it’ll be the best in class for JAK inhibitors right now,” Dr. Singh said in an interview. “A lot of that hinges on the safety of this drug. In terms of positioning, it depends on whether the [Food and Drug Administration] requires patients to have failed anti–[tumor necrosis factor] therapy before using this drug, like tofacitinib.”

That may depend on long-term data, he suggested.

“Right now, it is hard to comment on the relative safety of upadacitinib versus tofacitinib,” Dr. Singh said. “While the JAK1 selectivity may contribute to efficacy by allowing us to use a higher dose, it’s unclear whether the higher dose of this medication is any safer than tofacitinib. Longer term, 5- to 7-year registry studies of real-world data are warranted to examine risk of cardiovascular disease, thromboembolism, malignancy, and mortality with upadacitinib.

“How to sequence and position these therapies in real-world practice is a key question,” he concluded.

The study was supported by AbbVie. The investigators disclosed additional affiliations with Genentech, Ferring, AstraZeneca, and others. Dr. Axelrad has previously consulted for AbbVie. Dr. Singh has received research funding from AbbVie, Pfizer, and Janssen in the last 24 months, as well as personal fees from Pfizer for an ad hoc grant review.

For over a decade, the influential National Comprehensive Cancer Network (NCCN) has been recommending that men with low-risk prostate cancer be offered active surveillance as the lone “preferred” initial treatment option.

But the NCCN has now reversed this long-standing recommendation in the latest revision of its prostate cancer guideline.

The organization now recommends that low-risk disease be managed with either active surveillance or radiation therapy or surgery, with equal weight given to all three of these initial options.

The change is seen by some as a retreat to the past and was harshly criticized by many experts on Twitter. The complaints were voiced in unusually blunt and strong language for physicians.

“This is a terrible step back that impacts every urologist,” commented John Griffith, MD, of Hartford Healthcare, who practices in New Britain, Conn.

Dr. Griffith explained that he prints out the NCCN guidance with “every patient newly diagnosed” and that the preferred designation is a “huge help” in reassuring them about not treating low-risk disease initially.

In a Twitter thread, Benjamin Davies, MD, of the University of Pittsburgh, facetiously wondered if a time warp was at play: “To suggest for a millisecond that active surveillance isn’t the preferred method for low-risk men is bizarre thinking ... Is this 1980?”

“I’m baffled,” said Brian Chapin, MD, of MD Anderson Cancer Center, Houston, in another Twitter thread.

“This is ludicrous,” said Andrew Vickers, PhD, of Memorial Sloan Kettering Cancer Center in New York City in a tweet.

Alexander Kutikov, MD, of Fox Chase Cancer Center in Philadelphia, commented on Twitter that the change “seems off the rails…a bit stunned by this.”

Matthew Cooperberg, MD, of the University of California San Francisco, and Minhaj Siddiqui, MD, of the University of Maryland in Baltimore both called the move a “step backward.”

Many others also expressed disappointment in the NCCN, whose guidelines are hugely influential because of the role they play clinically as well as with payors and the legal system.

“A huge setback & frankly a disgrace for @NCCN and its processes,” commented Fox Chase’s Dr. Kutikov.

Stacy Loeb, MD, of NYU Langone Health in New York City, suggested the new guidance may stunt use of active surveillance in the United States. She tweeted: “The updated NCCN guideline certainly won’t help the lagging and heterogenous uptake of active surveillance in the U.S. We should be carefully expanding the pool for active surveillance, not narrowing it.”

The purpose of active surveillance is to avoid adverse events from treatment, which can be life-changing as they include incontinence and erectile dysfunction.

The rationale is that many men with low-risk prostate cancer may not need treatment for their disease, as the disease may be slow-growing and may never threaten their life. With active surveillance, men are instead monitored with blood tests, scans, and biopsies to watch for worsening disease, and treated only when there are signs of disease progression.

This active surveillance approach has grown in acceptance among American patients since 2010.

The concern now is that the change in guidance from the NCCN will lead to a reduction in active surveillance, and an increase in initial treatment with surgery and radiotherapy for low-risk disease, which is considered by many to be “overtreatment’ of this disease and may not be medically necessary.  

For example, UCSF’s Dr. Cooperberg said he feared that the changed guidance “will be used by urologists and radiation oncologists to justify overtreatment of low-risk disease.”

Dr. Kutikov agreed but described that possibility differently, citing the risk of lawsuits. He observed that without the NCCN’s “medico-legal buffer” of active surveillance as the preferred initial treatment, there are “further incentives” for overtreatment.

The new NCCN guidance also conflicts with the American Urological Association’s guidelines and dissolves what was once a mostly united front from the two major organizations on active surveillance and low-risk disease.

The AUA Guideline reads: “Clinicians should recommend active surveillance as the preferable care option for most low-risk localized prostate cancer patients (Moderate Recommendation; Evidence Level: Grade B)
 

Patients protest change in wording

Not surprisingly, the revised NCCN guidance was criticized by multiple patient advocacy groups, including Active Surveillance Patients International (ASPI), which wrote a letter to the NCCN protesting the change.

In that letter, the ASPI writes that active surveillance is now chosen as the initial approach for low-risk prostate cancer in about 90% of cases in some European nations, and in about 50% of cases in the United States. It also warns that eliminating the word “preferred” from the NCCN guidelines represents a retreat, and “will have repercussions far beyond what we may first conceive.” 

“Active surveillance should be the preferred choice to preserve quality of life for men with low-risk cancer,” the advocacy group states. “The PIVOT trials indicate for low-risk disease there is basically no advantage to intervention. Why would one risk the side effects if they knew that?”
 

Why now?

The NCCN’s move to alter its low-risk prostate cancer guidance is especially striking because, 11 years ago, the NCCN broke new ground in recommending active surveillance as the sole initial treatment option for low-risk men. (It was also the first guidelines group to recommend the same for very low-risk men.)

So why the change now? This news organization requested, but did not receive,  comment from the NCCN and its chair of the prostate cancer panel, Edward Schaeffer, MD, of Northwestern University in Chicago.  

However, on Twitter, Dr. Schaeffer hinted at what had turned the tables for the NCCN panel – the risk that, over time, some men with low-risk disease who are on active surveillance are reclassified on biopsy as having a higher risk.

He highlighted a 2020 study on that very subject from the University of California, San Francisco, published in the Journal of Urology. Those authors concluded that: “Given the heterogeneity of the disease, some tumors characterized as low risk may merit early treatment while others may be followed much less intensely over some time interval.”

Dr. Schaeffer tweeted: “I think this nicely sums up the low-risk space ...”

Experts reacting to Dr. Schaeffer’s tweet were not swayed.

Looking at additional measures such as genomic scores and PSA density, as advocated by Dr. Schaeffer via the posted 2020 study, is good for assessing individual risk, “but still, active surveillance is the preferred option for low risk,” said MD Anderson’s Dr. Chapin.

UCSF’s Dr. Cooperberg, who was a co-author on that 2020 Journal of Urology paper,  commented that the university’s urology department had “spent the past quarter century arguing active surveillance is ‘preferred’ for almost all low risk [disease]!”

“Many on active surveillance need treatment someday, but that does not justify immediate overtreatment,” he concluded.

A version of this article first appeared on Medscape.com.

For over a decade, the influential National Comprehensive Cancer Network (NCCN) has been recommending that men with low-risk prostate cancer be offered active surveillance as the lone “preferred” initial treatment option.

But the NCCN has now reversed this long-standing recommendation in the latest revision of its prostate cancer guideline.

The organization now recommends that low-risk disease be managed with either active surveillance or radiation therapy or surgery, with equal weight given to all three of these initial options.

The change is seen by some as a retreat to the past and was harshly criticized by many experts on Twitter. The complaints were voiced in unusually blunt and strong language for physicians.

“This is a terrible step back that impacts every urologist,” commented John Griffith, MD, of Hartford Healthcare, who practices in New Britain, Conn.

Dr. Griffith explained that he prints out the NCCN guidance with “every patient newly diagnosed” and that the preferred designation is a “huge help” in reassuring them about not treating low-risk disease initially.

In a Twitter thread, Benjamin Davies, MD, of the University of Pittsburgh, facetiously wondered if a time warp was at play: “To suggest for a millisecond that active surveillance isn’t the preferred method for low-risk men is bizarre thinking ... Is this 1980?”

“I’m baffled,” said Brian Chapin, MD, of MD Anderson Cancer Center, Houston, in another Twitter thread.

“This is ludicrous,” said Andrew Vickers, PhD, of Memorial Sloan Kettering Cancer Center in New York City in a tweet.

Alexander Kutikov, MD, of Fox Chase Cancer Center in Philadelphia, commented on Twitter that the change “seems off the rails…a bit stunned by this.”

Matthew Cooperberg, MD, of the University of California San Francisco, and Minhaj Siddiqui, MD, of the University of Maryland in Baltimore both called the move a “step backward.”

Many others also expressed disappointment in the NCCN, whose guidelines are hugely influential because of the role they play clinically as well as with payors and the legal system.

“A huge setback & frankly a disgrace for @NCCN and its processes,” commented Fox Chase’s Dr. Kutikov.

Stacy Loeb, MD, of NYU Langone Health in New York City, suggested the new guidance may stunt use of active surveillance in the United States. She tweeted: “The updated NCCN guideline certainly won’t help the lagging and heterogenous uptake of active surveillance in the U.S. We should be carefully expanding the pool for active surveillance, not narrowing it.”

The purpose of active surveillance is to avoid adverse events from treatment, which can be life-changing as they include incontinence and erectile dysfunction.

The rationale is that many men with low-risk prostate cancer may not need treatment for their disease, as the disease may be slow-growing and may never threaten their life. With active surveillance, men are instead monitored with blood tests, scans, and biopsies to watch for worsening disease, and treated only when there are signs of disease progression.

This active surveillance approach has grown in acceptance among American patients since 2010.

The concern now is that the change in guidance from the NCCN will lead to a reduction in active surveillance, and an increase in initial treatment with surgery and radiotherapy for low-risk disease, which is considered by many to be “overtreatment’ of this disease and may not be medically necessary.  

For example, UCSF’s Dr. Cooperberg said he feared that the changed guidance “will be used by urologists and radiation oncologists to justify overtreatment of low-risk disease.”

Dr. Kutikov agreed but described that possibility differently, citing the risk of lawsuits. He observed that without the NCCN’s “medico-legal buffer” of active surveillance as the preferred initial treatment, there are “further incentives” for overtreatment.

The new NCCN guidance also conflicts with the American Urological Association’s guidelines and dissolves what was once a mostly united front from the two major organizations on active surveillance and low-risk disease.

The AUA Guideline reads: “Clinicians should recommend active surveillance as the preferable care option for most low-risk localized prostate cancer patients (Moderate Recommendation; Evidence Level: Grade B)
 

Patients protest change in wording

Not surprisingly, the revised NCCN guidance was criticized by multiple patient advocacy groups, including Active Surveillance Patients International (ASPI), which wrote a letter to the NCCN protesting the change.

In that letter, the ASPI writes that active surveillance is now chosen as the initial approach for low-risk prostate cancer in about 90% of cases in some European nations, and in about 50% of cases in the United States. It also warns that eliminating the word “preferred” from the NCCN guidelines represents a retreat, and “will have repercussions far beyond what we may first conceive.” 

“Active surveillance should be the preferred choice to preserve quality of life for men with low-risk cancer,” the advocacy group states. “The PIVOT trials indicate for low-risk disease there is basically no advantage to intervention. Why would one risk the side effects if they knew that?”
 

Why now?

The NCCN’s move to alter its low-risk prostate cancer guidance is especially striking because, 11 years ago, the NCCN broke new ground in recommending active surveillance as the sole initial treatment option for low-risk men. (It was also the first guidelines group to recommend the same for very low-risk men.)

So why the change now? This news organization requested, but did not receive,  comment from the NCCN and its chair of the prostate cancer panel, Edward Schaeffer, MD, of Northwestern University in Chicago.  

However, on Twitter, Dr. Schaeffer hinted at what had turned the tables for the NCCN panel – the risk that, over time, some men with low-risk disease who are on active surveillance are reclassified on biopsy as having a higher risk.

He highlighted a 2020 study on that very subject from the University of California, San Francisco, published in the Journal of Urology. Those authors concluded that: “Given the heterogeneity of the disease, some tumors characterized as low risk may merit early treatment while others may be followed much less intensely over some time interval.”

Dr. Schaeffer tweeted: “I think this nicely sums up the low-risk space ...”

Experts reacting to Dr. Schaeffer’s tweet were not swayed.

Looking at additional measures such as genomic scores and PSA density, as advocated by Dr. Schaeffer via the posted 2020 study, is good for assessing individual risk, “but still, active surveillance is the preferred option for low risk,” said MD Anderson’s Dr. Chapin.

UCSF’s Dr. Cooperberg, who was a co-author on that 2020 Journal of Urology paper,  commented that the university’s urology department had “spent the past quarter century arguing active surveillance is ‘preferred’ for almost all low risk [disease]!”

“Many on active surveillance need treatment someday, but that does not justify immediate overtreatment,” he concluded.

A version of this article first appeared on Medscape.com.

For over a decade, the influential National Comprehensive Cancer Network (NCCN) has been recommending that men with low-risk prostate cancer be offered active surveillance as the lone “preferred” initial treatment option.

But the NCCN has now reversed this long-standing recommendation in the latest revision of its prostate cancer guideline.

The organization now recommends that low-risk disease be managed with either active surveillance or radiation therapy or surgery, with equal weight given to all three of these initial options.

The change is seen by some as a retreat to the past and was harshly criticized by many experts on Twitter. The complaints were voiced in unusually blunt and strong language for physicians.

“This is a terrible step back that impacts every urologist,” commented John Griffith, MD, of Hartford Healthcare, who practices in New Britain, Conn.

Dr. Griffith explained that he prints out the NCCN guidance with “every patient newly diagnosed” and that the preferred designation is a “huge help” in reassuring them about not treating low-risk disease initially.

In a Twitter thread, Benjamin Davies, MD, of the University of Pittsburgh, facetiously wondered if a time warp was at play: “To suggest for a millisecond that active surveillance isn’t the preferred method for low-risk men is bizarre thinking ... Is this 1980?”

“I’m baffled,” said Brian Chapin, MD, of MD Anderson Cancer Center, Houston, in another Twitter thread.

“This is ludicrous,” said Andrew Vickers, PhD, of Memorial Sloan Kettering Cancer Center in New York City in a tweet.

Alexander Kutikov, MD, of Fox Chase Cancer Center in Philadelphia, commented on Twitter that the change “seems off the rails…a bit stunned by this.”

Matthew Cooperberg, MD, of the University of California San Francisco, and Minhaj Siddiqui, MD, of the University of Maryland in Baltimore both called the move a “step backward.”

Many others also expressed disappointment in the NCCN, whose guidelines are hugely influential because of the role they play clinically as well as with payors and the legal system.

“A huge setback & frankly a disgrace for @NCCN and its processes,” commented Fox Chase’s Dr. Kutikov.

Stacy Loeb, MD, of NYU Langone Health in New York City, suggested the new guidance may stunt use of active surveillance in the United States. She tweeted: “The updated NCCN guideline certainly won’t help the lagging and heterogenous uptake of active surveillance in the U.S. We should be carefully expanding the pool for active surveillance, not narrowing it.”

The purpose of active surveillance is to avoid adverse events from treatment, which can be life-changing as they include incontinence and erectile dysfunction.

The rationale is that many men with low-risk prostate cancer may not need treatment for their disease, as the disease may be slow-growing and may never threaten their life. With active surveillance, men are instead monitored with blood tests, scans, and biopsies to watch for worsening disease, and treated only when there are signs of disease progression.

This active surveillance approach has grown in acceptance among American patients since 2010.

The concern now is that the change in guidance from the NCCN will lead to a reduction in active surveillance, and an increase in initial treatment with surgery and radiotherapy for low-risk disease, which is considered by many to be “overtreatment’ of this disease and may not be medically necessary.  

For example, UCSF’s Dr. Cooperberg said he feared that the changed guidance “will be used by urologists and radiation oncologists to justify overtreatment of low-risk disease.”

Dr. Kutikov agreed but described that possibility differently, citing the risk of lawsuits. He observed that without the NCCN’s “medico-legal buffer” of active surveillance as the preferred initial treatment, there are “further incentives” for overtreatment.

The new NCCN guidance also conflicts with the American Urological Association’s guidelines and dissolves what was once a mostly united front from the two major organizations on active surveillance and low-risk disease.

The AUA Guideline reads: “Clinicians should recommend active surveillance as the preferable care option for most low-risk localized prostate cancer patients (Moderate Recommendation; Evidence Level: Grade B)
 

Patients protest change in wording

Not surprisingly, the revised NCCN guidance was criticized by multiple patient advocacy groups, including Active Surveillance Patients International (ASPI), which wrote a letter to the NCCN protesting the change.

In that letter, the ASPI writes that active surveillance is now chosen as the initial approach for low-risk prostate cancer in about 90% of cases in some European nations, and in about 50% of cases in the United States. It also warns that eliminating the word “preferred” from the NCCN guidelines represents a retreat, and “will have repercussions far beyond what we may first conceive.” 

“Active surveillance should be the preferred choice to preserve quality of life for men with low-risk cancer,” the advocacy group states. “The PIVOT trials indicate for low-risk disease there is basically no advantage to intervention. Why would one risk the side effects if they knew that?”
 

Why now?

The NCCN’s move to alter its low-risk prostate cancer guidance is especially striking because, 11 years ago, the NCCN broke new ground in recommending active surveillance as the sole initial treatment option for low-risk men. (It was also the first guidelines group to recommend the same for very low-risk men.)

So why the change now? This news organization requested, but did not receive,  comment from the NCCN and its chair of the prostate cancer panel, Edward Schaeffer, MD, of Northwestern University in Chicago.  

However, on Twitter, Dr. Schaeffer hinted at what had turned the tables for the NCCN panel – the risk that, over time, some men with low-risk disease who are on active surveillance are reclassified on biopsy as having a higher risk.

He highlighted a 2020 study on that very subject from the University of California, San Francisco, published in the Journal of Urology. Those authors concluded that: “Given the heterogeneity of the disease, some tumors characterized as low risk may merit early treatment while others may be followed much less intensely over some time interval.”

Dr. Schaeffer tweeted: “I think this nicely sums up the low-risk space ...”

Experts reacting to Dr. Schaeffer’s tweet were not swayed.

Looking at additional measures such as genomic scores and PSA density, as advocated by Dr. Schaeffer via the posted 2020 study, is good for assessing individual risk, “but still, active surveillance is the preferred option for low risk,” said MD Anderson’s Dr. Chapin.

UCSF’s Dr. Cooperberg, who was a co-author on that 2020 Journal of Urology paper,  commented that the university’s urology department had “spent the past quarter century arguing active surveillance is ‘preferred’ for almost all low risk [disease]!”

“Many on active surveillance need treatment someday, but that does not justify immediate overtreatment,” he concluded.

A version of this article first appeared on Medscape.com.

Extended follow-up of the PRAGUE-17 trial suggests left atrial appendage closure (LAAC) remains noninferior to direct-acting oral anticoagulants (DOACs) with regard to major cardiovascular and neurologic events in high-risk patients with atrial fibrillation.

At a median follow-up of 3.5 years, the annualized rate of the primary outcome – a composite of stroke, transient ischemic attack (TIA), systemic embolism, cardiovascular death, clinically relevant bleeding, or significant procedure- or device-related complications – was 8.6% in patients who underwent LAAC and 11.9% in those managed with DOACs (P value for noninferiority = .006).

The study was not powered to assess the individual components, but most were similar between the LAAC and DOAC groups, including cardiovascular death (20 vs. 30 events) and all stroke/TIA (16 vs. 18 events).

Nonprocedural clinically relevant bleeding was lower with LAAC (23 vs. 40 events; annualized rate, 3.4% vs. 5.9%; P = .039), said Pavel Osmancik, MD, PhD, Charles University and University Hospital Kralovske Vinohrady, both in Prague.

The data were presented at the Transcatheter Cardiovascular Therapeutics annual meeting, held virtually and live in Orlando and sponsored by the Cardiovascular Research Foundation, and was published simultaneously in the Journal of the American College of Cardiology.

The results are generally in line with those reported in 2020 with an average follow-up of 20 months, when the annualized primary event rate was 11% with LAAC and 13% with DOACs, also known as novel OACs (NOACs).

The trial randomly assigned 415 patients to LAAC with the Amulet (Abbott Vascular) or Watchman/Watchman FLX devices (Boston Scientific) or to rivaroxaban, dabigatran, or preferably apixaban (96%). The modified intention-to-treat analysis included 201 patients in each group, with follow-up extending to 4.3 years in the LAAC group and 4.2 years in the DOAC group.

Dr. Osmancik said the trial enrolled a very-high-risk atrial fibrillation cohort, citing a CHA2DS2-VASc score of 4.7 in both groups and a HAS-BLED score of 3.0-3.1. More than half of the LAAC group (54.2%) and 47.3% of the DOAC group had a history of bleeding or bleeding predisposition.

During a discussion of the results, the panel questioned whether the continuing divergence of the primary event curves at 4 years was potentially related to the effect of noncompliance to the NOACs over time.

Dr. Osmancik replied: “We didn’t do any medication look among the patients, but I don’t think that the number of patients who stopped the NOAC treatment was too high because the rate of strokes was very similar to that in the NOAC trials.”

He reported that 26 patients in the DOAC group permanently stopped their DOAC during follow-up; 15 (58%) because of clinically relevant bleeding, and 13 crossed over to LAAC. Of the 13 patients, 12 cases were successful with dual antiplatelet therapy for 3 months.

In the LAAC group, 17 patients started a DOAC during follow-up. Of these, three (18%) initiated DOAC treatment because of device-related thrombus (DRT) on transesophageal echocardiography, three (18%) because of a peridevice leak (PDL), and five (29%) because of a stroke/TIA.

“Given the observed trend of significantly increased nonprocedural clinically relevant bleeding in the NOAC arm, it is likely that late bleeding events will increasingly favor LAAC over time,” Faisal Merchant, MD, Emory University, Atlanta, wrote in an accompanying editorial.

NOACs, he noted, have important indications beyond prevention of left atrial appendage thrombi, including prevention of non-LAA sources of stroke/systemic embolism (SSE) and treatment of venous thromboembolism. “If significant numbers of patients treated with LAAC end up on anticoagulation in the long run, the benefits of LAAC are likely to be attenuated.”

Although PRAGUE-17 provides some insights into the longer-term indications for resuming anticoagulation in patients previously treated with LAAC, Dr. Merchant said the trial is a “real missed opportunity” in terms of understanding late device-associated risks. Unfortunately, two-thirds of the follow-up transesophageal echocardiograms were canceled because of the COVID-19 pandemic.

“Although the incidence of late DRT and PDL isn’t known, the longer-term PRAGUE-17 data are helpful in demonstrating that rates of SSE remain similar in the LAAC and NOAC groups over time, without any obvious signal of late ischemic events in the LAAC group,” he wrote.

The editorialist also called attention to the “often overlooked” issue of aspirin adherence in long-term medical therapy. Although patients treated with LAAC typically remain on aspirin indefinitely, the percentage who discontinue long-term aspirin is not well described and is not reported in PRAGUE-17. In the AVERROES trial, comparing aspirin with apixaban in patients with atrial fibrillation, however, 20.5% of patients permanently discontinued aspirin at 2 years, compared with only 17.9% on apixaban.

“It is plausible that discontinuation of aspirin may contribute to late ischemic events in patients treated with LAAC, potentially by increasing the risk of late DRT or through other mechanisms,” Dr. Merchant wrote. “Adherence to, and the impact of, long-term antiplatelet therapy should be a focus of future LAAC studies.”

The study was funded by a research grant from the Ministry of Health, Czech Republic. Dr. Osmancik reported occasional speaking honoraria from Bayer and Abbott. Dr. Merchant disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Extended follow-up of the PRAGUE-17 trial suggests left atrial appendage closure (LAAC) remains noninferior to direct-acting oral anticoagulants (DOACs) with regard to major cardiovascular and neurologic events in high-risk patients with atrial fibrillation.

At a median follow-up of 3.5 years, the annualized rate of the primary outcome – a composite of stroke, transient ischemic attack (TIA), systemic embolism, cardiovascular death, clinically relevant bleeding, or significant procedure- or device-related complications – was 8.6% in patients who underwent LAAC and 11.9% in those managed with DOACs (P value for noninferiority = .006).

The study was not powered to assess the individual components, but most were similar between the LAAC and DOAC groups, including cardiovascular death (20 vs. 30 events) and all stroke/TIA (16 vs. 18 events).

Nonprocedural clinically relevant bleeding was lower with LAAC (23 vs. 40 events; annualized rate, 3.4% vs. 5.9%; P = .039), said Pavel Osmancik, MD, PhD, Charles University and University Hospital Kralovske Vinohrady, both in Prague.

The data were presented at the Transcatheter Cardiovascular Therapeutics annual meeting, held virtually and live in Orlando and sponsored by the Cardiovascular Research Foundation, and was published simultaneously in the Journal of the American College of Cardiology.

The results are generally in line with those reported in 2020 with an average follow-up of 20 months, when the annualized primary event rate was 11% with LAAC and 13% with DOACs, also known as novel OACs (NOACs).

The trial randomly assigned 415 patients to LAAC with the Amulet (Abbott Vascular) or Watchman/Watchman FLX devices (Boston Scientific) or to rivaroxaban, dabigatran, or preferably apixaban (96%). The modified intention-to-treat analysis included 201 patients in each group, with follow-up extending to 4.3 years in the LAAC group and 4.2 years in the DOAC group.

Dr. Osmancik said the trial enrolled a very-high-risk atrial fibrillation cohort, citing a CHA2DS2-VASc score of 4.7 in both groups and a HAS-BLED score of 3.0-3.1. More than half of the LAAC group (54.2%) and 47.3% of the DOAC group had a history of bleeding or bleeding predisposition.

During a discussion of the results, the panel questioned whether the continuing divergence of the primary event curves at 4 years was potentially related to the effect of noncompliance to the NOACs over time.

Dr. Osmancik replied: “We didn’t do any medication look among the patients, but I don’t think that the number of patients who stopped the NOAC treatment was too high because the rate of strokes was very similar to that in the NOAC trials.”

He reported that 26 patients in the DOAC group permanently stopped their DOAC during follow-up; 15 (58%) because of clinically relevant bleeding, and 13 crossed over to LAAC. Of the 13 patients, 12 cases were successful with dual antiplatelet therapy for 3 months.

In the LAAC group, 17 patients started a DOAC during follow-up. Of these, three (18%) initiated DOAC treatment because of device-related thrombus (DRT) on transesophageal echocardiography, three (18%) because of a peridevice leak (PDL), and five (29%) because of a stroke/TIA.

“Given the observed trend of significantly increased nonprocedural clinically relevant bleeding in the NOAC arm, it is likely that late bleeding events will increasingly favor LAAC over time,” Faisal Merchant, MD, Emory University, Atlanta, wrote in an accompanying editorial.

NOACs, he noted, have important indications beyond prevention of left atrial appendage thrombi, including prevention of non-LAA sources of stroke/systemic embolism (SSE) and treatment of venous thromboembolism. “If significant numbers of patients treated with LAAC end up on anticoagulation in the long run, the benefits of LAAC are likely to be attenuated.”

Although PRAGUE-17 provides some insights into the longer-term indications for resuming anticoagulation in patients previously treated with LAAC, Dr. Merchant said the trial is a “real missed opportunity” in terms of understanding late device-associated risks. Unfortunately, two-thirds of the follow-up transesophageal echocardiograms were canceled because of the COVID-19 pandemic.

“Although the incidence of late DRT and PDL isn’t known, the longer-term PRAGUE-17 data are helpful in demonstrating that rates of SSE remain similar in the LAAC and NOAC groups over time, without any obvious signal of late ischemic events in the LAAC group,” he wrote.

The editorialist also called attention to the “often overlooked” issue of aspirin adherence in long-term medical therapy. Although patients treated with LAAC typically remain on aspirin indefinitely, the percentage who discontinue long-term aspirin is not well described and is not reported in PRAGUE-17. In the AVERROES trial, comparing aspirin with apixaban in patients with atrial fibrillation, however, 20.5% of patients permanently discontinued aspirin at 2 years, compared with only 17.9% on apixaban.

“It is plausible that discontinuation of aspirin may contribute to late ischemic events in patients treated with LAAC, potentially by increasing the risk of late DRT or through other mechanisms,” Dr. Merchant wrote. “Adherence to, and the impact of, long-term antiplatelet therapy should be a focus of future LAAC studies.”

The study was funded by a research grant from the Ministry of Health, Czech Republic. Dr. Osmancik reported occasional speaking honoraria from Bayer and Abbott. Dr. Merchant disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Extended follow-up of the PRAGUE-17 trial suggests left atrial appendage closure (LAAC) remains noninferior to direct-acting oral anticoagulants (DOACs) with regard to major cardiovascular and neurologic events in high-risk patients with atrial fibrillation.

At a median follow-up of 3.5 years, the annualized rate of the primary outcome – a composite of stroke, transient ischemic attack (TIA), systemic embolism, cardiovascular death, clinically relevant bleeding, or significant procedure- or device-related complications – was 8.6% in patients who underwent LAAC and 11.9% in those managed with DOACs (P value for noninferiority = .006).

The study was not powered to assess the individual components, but most were similar between the LAAC and DOAC groups, including cardiovascular death (20 vs. 30 events) and all stroke/TIA (16 vs. 18 events).

Nonprocedural clinically relevant bleeding was lower with LAAC (23 vs. 40 events; annualized rate, 3.4% vs. 5.9%; P = .039), said Pavel Osmancik, MD, PhD, Charles University and University Hospital Kralovske Vinohrady, both in Prague.

The data were presented at the Transcatheter Cardiovascular Therapeutics annual meeting, held virtually and live in Orlando and sponsored by the Cardiovascular Research Foundation, and was published simultaneously in the Journal of the American College of Cardiology.

The results are generally in line with those reported in 2020 with an average follow-up of 20 months, when the annualized primary event rate was 11% with LAAC and 13% with DOACs, also known as novel OACs (NOACs).

The trial randomly assigned 415 patients to LAAC with the Amulet (Abbott Vascular) or Watchman/Watchman FLX devices (Boston Scientific) or to rivaroxaban, dabigatran, or preferably apixaban (96%). The modified intention-to-treat analysis included 201 patients in each group, with follow-up extending to 4.3 years in the LAAC group and 4.2 years in the DOAC group.

Dr. Osmancik said the trial enrolled a very-high-risk atrial fibrillation cohort, citing a CHA2DS2-VASc score of 4.7 in both groups and a HAS-BLED score of 3.0-3.1. More than half of the LAAC group (54.2%) and 47.3% of the DOAC group had a history of bleeding or bleeding predisposition.

During a discussion of the results, the panel questioned whether the continuing divergence of the primary event curves at 4 years was potentially related to the effect of noncompliance to the NOACs over time.

Dr. Osmancik replied: “We didn’t do any medication look among the patients, but I don’t think that the number of patients who stopped the NOAC treatment was too high because the rate of strokes was very similar to that in the NOAC trials.”

He reported that 26 patients in the DOAC group permanently stopped their DOAC during follow-up; 15 (58%) because of clinically relevant bleeding, and 13 crossed over to LAAC. Of the 13 patients, 12 cases were successful with dual antiplatelet therapy for 3 months.

In the LAAC group, 17 patients started a DOAC during follow-up. Of these, three (18%) initiated DOAC treatment because of device-related thrombus (DRT) on transesophageal echocardiography, three (18%) because of a peridevice leak (PDL), and five (29%) because of a stroke/TIA.

“Given the observed trend of significantly increased nonprocedural clinically relevant bleeding in the NOAC arm, it is likely that late bleeding events will increasingly favor LAAC over time,” Faisal Merchant, MD, Emory University, Atlanta, wrote in an accompanying editorial.

NOACs, he noted, have important indications beyond prevention of left atrial appendage thrombi, including prevention of non-LAA sources of stroke/systemic embolism (SSE) and treatment of venous thromboembolism. “If significant numbers of patients treated with LAAC end up on anticoagulation in the long run, the benefits of LAAC are likely to be attenuated.”

Although PRAGUE-17 provides some insights into the longer-term indications for resuming anticoagulation in patients previously treated with LAAC, Dr. Merchant said the trial is a “real missed opportunity” in terms of understanding late device-associated risks. Unfortunately, two-thirds of the follow-up transesophageal echocardiograms were canceled because of the COVID-19 pandemic.

“Although the incidence of late DRT and PDL isn’t known, the longer-term PRAGUE-17 data are helpful in demonstrating that rates of SSE remain similar in the LAAC and NOAC groups over time, without any obvious signal of late ischemic events in the LAAC group,” he wrote.

The editorialist also called attention to the “often overlooked” issue of aspirin adherence in long-term medical therapy. Although patients treated with LAAC typically remain on aspirin indefinitely, the percentage who discontinue long-term aspirin is not well described and is not reported in PRAGUE-17. In the AVERROES trial, comparing aspirin with apixaban in patients with atrial fibrillation, however, 20.5% of patients permanently discontinued aspirin at 2 years, compared with only 17.9% on apixaban.

“It is plausible that discontinuation of aspirin may contribute to late ischemic events in patients treated with LAAC, potentially by increasing the risk of late DRT or through other mechanisms,” Dr. Merchant wrote. “Adherence to, and the impact of, long-term antiplatelet therapy should be a focus of future LAAC studies.”

The study was funded by a research grant from the Ministry of Health, Czech Republic. Dr. Osmancik reported occasional speaking honoraria from Bayer and Abbott. Dr. Merchant disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Background: Although troponin is the preferred biomarker to indicate acute myocardial infarction, little is known about the implications of elevated troponin in the absence of plaque rupture.

Dr. Bhasin is a hospitalist at Northwestern Memorial Hospital and Lurie Children’s Hospital and assistant professor of medicine, Feinberg School of Medicine, all in Chicago.

Background: Although troponin is the preferred biomarker to indicate acute myocardial infarction, little is known about the implications of elevated troponin in the absence of plaque rupture.

Dr. Bhasin is a hospitalist at Northwestern Memorial Hospital and Lurie Children’s Hospital and assistant professor of medicine, Feinberg School of Medicine, all in Chicago.

Background: Although troponin is the preferred biomarker to indicate acute myocardial infarction, little is known about the implications of elevated troponin in the absence of plaque rupture.

Dr. Bhasin is a hospitalist at Northwestern Memorial Hospital and Lurie Children’s Hospital and assistant professor of medicine, Feinberg School of Medicine, all in Chicago.

On day 1 of her fellowship, Francesca C. Duncan, MD, was blindsided by her first patient.

The patient, a White man who was accompanied by his wife, sat in the exam room with his sunglasses on.

“I remember him saying, ‘I need to take off my sunglasses so you don’t look so Black,’” said Dr. Duncan, a pulmonologist and intensivist at Indiana University, Indianapolis, who has a specialty in lung cancer disparities.

The patient proceeded to grill her about her experience and training. He asked where she attended college and mocked her degree from a historically Black university. His wife sat there, silent.

Dr. Duncan was shocked by the fact that she still had to defend her credentials.

“I just kind of felt like at that point in my training, my title would have earned me more respect,” said Dr. Duncan, now an assistant professor after recently completing a 3-year fellowship in pulmonary and critical care medicine. “I thought at some point [the racism and discrimination] would stop, but after all that training, all that late-night studying, I still had to prove myself.”

Unfortunately, Dr. Duncan’s experience in fellowship is not unique.

A recent survey of hematology and oncology fellows revealed that medical trainees routinely encounter discrimination during their training.

The 17 fellows who were anonymously interviewed in the survey all recalled experiencing or witnessing discriminatory behaviors during their fellowship, mostly from patients. These encounters rarely come to light. Only one respondent officially reported an incident.

The findings, published online November 8 in JAMA Network Open, underscore the need for graduate medical education programs to improve learning environments and support for trainees, lead author Rahma M. Warsame, MD, and colleagues say .
 

Discrimination at work

Initially, Dr. Warsame and co–principal investigator Katharine Price, MD, were tasked with developing strategies to mitigate instances of racism and bias that fellows encountered during training, but both felt it was critical to understand the experiences of their trainees first.

Out of 34 fellows and recent graduates of the hematology and oncology fellowship program of the Mayo Clinic, Rochester, Minn., 20 consented to participate in the study. Of those, 17 were interviewed between July and November 2018. Among the 17 interviewees, six were Asian, two were Black, three were Hispanic, two were multiracial, and four were White.

Dr. Warsame and colleagues found that everyone reported experiencing or witnessing biased or discriminatory events. The majority of these offenses were committed by patients, not faculty or other employees. The researchers largely interpreted most of the incidents as microaggressions.

From the interviews, the researchers identified six central themes. Among them: foreign fellows and U.S.-born trainees being perceived or made to feel like outsiders; inappropriate comments being made toward female employees about their looks, credentials, or marital status; lack of action after reporting incidents or concerns that reporting such incidents would be futile; and strategies fellows used to cope after negative interactions.

One interviewee said, “I was fired by a patient because I have an accent.” Another said that when she is interviewing for jobs, she is always asked if she has children: “Maybe they’re asking in an innocuous manner, but I always feel like people worry. Is this person going to take maternity leave and be less available for work?”

For Dr. Warsame, “the idea that American citizens were frequently made to feel like they do not belong was surprising.”

Not surprising to Dr. Warsame, however, was the importance of fostering diversity and inclusion during fellowship years. Fellows often noted that greater diversity within the program helped create a more inclusive environment.

“[What’s] important to reinforce is the value of creating platforms for honest discussion and intentionally seeking fellows’ voices and perspectives, which in turn makes them feel like they belong,” Dr. Warsame said.

Still, the researchers found that fellows often did not report incidents of discrimination or bias. Only six trainees were aware of policies for reporting patient misconduct or discrimination, and only one ever reported an incident.
 

Where’s the support?

For Dr. Duncan, her encounter 3 years ago with the patient with sunglasses wasn’t her first experience of discrimination on the job — or her last.

Although hurtful in the moment, she had the wherewithal to report the incident to her attending physician, who was equally shocked. Initially unsure of how to handle it, the attending ultimately stepped up and provided “immense support,” Dr. Duncan said

The issue was brought to the attention of the program director, who took swift action. The patient was documented as “disruptive,” informed of that status in writing, and was banned from receiving treatment from trainees at the center, although Dr. Duncan noted he still received the medical care he needed.

Often, however, fellows who report incidents of discrimination and racism receive little support. According to Dr. Warsame and colleagues, most trainees don’t bother reporting these experiences because they believe that doing so would be futile.

“Concerns about reporting included jeopardizing future employability, risk of retaliation, and challenges reporting experiences that could be perceived as subjective and difficult to prove,” the authors write.

For instance, one interviewee said: “I’m afraid to report these things because there’s gonna be repercussions. There’s no way it’s gonna be anonymous.... I just have to toughen up and, you know, get used [to it].”

Dr. Warsame added, “A major challenge for trainees was that they often felt unheard, and at the time, there was no formal debrief regarding discrimination issues when they arose.”

These instances of bias have implications for trainee well-being. In a 2019 study, discrimination that physicians and students experienced during training had adverse effects on their emotional health. Responses from 50 trainees and physicians revealed a wide range of discriminatory experiences, including patients rejecting care and spewing racist, sexist, or homophobic epithets. Many physicians were uncertain about how to respond effectively and appropriately.

Since that study was published and after having completed her own fellowship, Dr. Duncan said she has seen some change for the better.

“There is a lot more awareness around this, and programs are trying to do better in recognizing and responding to incidents,” she said. She noted that it’s important to ensure that those who are directly affected by discriminatory behaviors aren’t left to do all of the “heavy lifting” of addressing and resolving the issues.

The weight of discriminatory incidents, from microaggressions to overt racism, is cumulative and can adversely affect a person’s career. “It’s exhausting -- we need support,” she said.

The Mayo Clinic is working to ensure that trainees receive support. “The study has prompted communication workshops and faculty development to better equip trainees with strategies to address [and report] patients who behave or display disrespectful or discriminatory behavior,” Dr. Warsame said.

She and her colleagues noted that the anonymous hotline used for the survey cultivated a safe environment for candid discussions and that such an approach is “feasible and effective to explore sensitive topics and scalable to various geographic locations and different medical specialties.”

“We recognize that our program must seek this feedback regularly and ensure we keep a finger on the pulse of our trainees,” Dr. Warsame added.

Dr. Warsame and Dr. Duncan have disclosed no relevant financial relationships. Dr. Duncan noted that her views and comments are her own and do not necessarily reflect those of her institution.

A version of this article first appeared on Medscape.com.

On day 1 of her fellowship, Francesca C. Duncan, MD, was blindsided by her first patient.

The patient, a White man who was accompanied by his wife, sat in the exam room with his sunglasses on.

“I remember him saying, ‘I need to take off my sunglasses so you don’t look so Black,’” said Dr. Duncan, a pulmonologist and intensivist at Indiana University, Indianapolis, who has a specialty in lung cancer disparities.

The patient proceeded to grill her about her experience and training. He asked where she attended college and mocked her degree from a historically Black university. His wife sat there, silent.

Dr. Duncan was shocked by the fact that she still had to defend her credentials.

“I just kind of felt like at that point in my training, my title would have earned me more respect,” said Dr. Duncan, now an assistant professor after recently completing a 3-year fellowship in pulmonary and critical care medicine. “I thought at some point [the racism and discrimination] would stop, but after all that training, all that late-night studying, I still had to prove myself.”

Unfortunately, Dr. Duncan’s experience in fellowship is not unique.

A recent survey of hematology and oncology fellows revealed that medical trainees routinely encounter discrimination during their training.

The 17 fellows who were anonymously interviewed in the survey all recalled experiencing or witnessing discriminatory behaviors during their fellowship, mostly from patients. These encounters rarely come to light. Only one respondent officially reported an incident.

The findings, published online November 8 in JAMA Network Open, underscore the need for graduate medical education programs to improve learning environments and support for trainees, lead author Rahma M. Warsame, MD, and colleagues say .
 

Discrimination at work

Initially, Dr. Warsame and co–principal investigator Katharine Price, MD, were tasked with developing strategies to mitigate instances of racism and bias that fellows encountered during training, but both felt it was critical to understand the experiences of their trainees first.

Out of 34 fellows and recent graduates of the hematology and oncology fellowship program of the Mayo Clinic, Rochester, Minn., 20 consented to participate in the study. Of those, 17 were interviewed between July and November 2018. Among the 17 interviewees, six were Asian, two were Black, three were Hispanic, two were multiracial, and four were White.

Dr. Warsame and colleagues found that everyone reported experiencing or witnessing biased or discriminatory events. The majority of these offenses were committed by patients, not faculty or other employees. The researchers largely interpreted most of the incidents as microaggressions.

From the interviews, the researchers identified six central themes. Among them: foreign fellows and U.S.-born trainees being perceived or made to feel like outsiders; inappropriate comments being made toward female employees about their looks, credentials, or marital status; lack of action after reporting incidents or concerns that reporting such incidents would be futile; and strategies fellows used to cope after negative interactions.

One interviewee said, “I was fired by a patient because I have an accent.” Another said that when she is interviewing for jobs, she is always asked if she has children: “Maybe they’re asking in an innocuous manner, but I always feel like people worry. Is this person going to take maternity leave and be less available for work?”

For Dr. Warsame, “the idea that American citizens were frequently made to feel like they do not belong was surprising.”

Not surprising to Dr. Warsame, however, was the importance of fostering diversity and inclusion during fellowship years. Fellows often noted that greater diversity within the program helped create a more inclusive environment.

“[What’s] important to reinforce is the value of creating platforms for honest discussion and intentionally seeking fellows’ voices and perspectives, which in turn makes them feel like they belong,” Dr. Warsame said.

Still, the researchers found that fellows often did not report incidents of discrimination or bias. Only six trainees were aware of policies for reporting patient misconduct or discrimination, and only one ever reported an incident.
 

Where’s the support?

For Dr. Duncan, her encounter 3 years ago with the patient with sunglasses wasn’t her first experience of discrimination on the job — or her last.

Although hurtful in the moment, she had the wherewithal to report the incident to her attending physician, who was equally shocked. Initially unsure of how to handle it, the attending ultimately stepped up and provided “immense support,” Dr. Duncan said

The issue was brought to the attention of the program director, who took swift action. The patient was documented as “disruptive,” informed of that status in writing, and was banned from receiving treatment from trainees at the center, although Dr. Duncan noted he still received the medical care he needed.

Often, however, fellows who report incidents of discrimination and racism receive little support. According to Dr. Warsame and colleagues, most trainees don’t bother reporting these experiences because they believe that doing so would be futile.

“Concerns about reporting included jeopardizing future employability, risk of retaliation, and challenges reporting experiences that could be perceived as subjective and difficult to prove,” the authors write.

For instance, one interviewee said: “I’m afraid to report these things because there’s gonna be repercussions. There’s no way it’s gonna be anonymous.... I just have to toughen up and, you know, get used [to it].”

Dr. Warsame added, “A major challenge for trainees was that they often felt unheard, and at the time, there was no formal debrief regarding discrimination issues when they arose.”

These instances of bias have implications for trainee well-being. In a 2019 study, discrimination that physicians and students experienced during training had adverse effects on their emotional health. Responses from 50 trainees and physicians revealed a wide range of discriminatory experiences, including patients rejecting care and spewing racist, sexist, or homophobic epithets. Many physicians were uncertain about how to respond effectively and appropriately.

Since that study was published and after having completed her own fellowship, Dr. Duncan said she has seen some change for the better.

“There is a lot more awareness around this, and programs are trying to do better in recognizing and responding to incidents,” she said. She noted that it’s important to ensure that those who are directly affected by discriminatory behaviors aren’t left to do all of the “heavy lifting” of addressing and resolving the issues.

The weight of discriminatory incidents, from microaggressions to overt racism, is cumulative and can adversely affect a person’s career. “It’s exhausting -- we need support,” she said.

The Mayo Clinic is working to ensure that trainees receive support. “The study has prompted communication workshops and faculty development to better equip trainees with strategies to address [and report] patients who behave or display disrespectful or discriminatory behavior,” Dr. Warsame said.

She and her colleagues noted that the anonymous hotline used for the survey cultivated a safe environment for candid discussions and that such an approach is “feasible and effective to explore sensitive topics and scalable to various geographic locations and different medical specialties.”

“We recognize that our program must seek this feedback regularly and ensure we keep a finger on the pulse of our trainees,” Dr. Warsame added.

Dr. Warsame and Dr. Duncan have disclosed no relevant financial relationships. Dr. Duncan noted that her views and comments are her own and do not necessarily reflect those of her institution.

A version of this article first appeared on Medscape.com.

On day 1 of her fellowship, Francesca C. Duncan, MD, was blindsided by her first patient.

The patient, a White man who was accompanied by his wife, sat in the exam room with his sunglasses on.

“I remember him saying, ‘I need to take off my sunglasses so you don’t look so Black,’” said Dr. Duncan, a pulmonologist and intensivist at Indiana University, Indianapolis, who has a specialty in lung cancer disparities.

The patient proceeded to grill her about her experience and training. He asked where she attended college and mocked her degree from a historically Black university. His wife sat there, silent.

Dr. Duncan was shocked by the fact that she still had to defend her credentials.

“I just kind of felt like at that point in my training, my title would have earned me more respect,” said Dr. Duncan, now an assistant professor after recently completing a 3-year fellowship in pulmonary and critical care medicine. “I thought at some point [the racism and discrimination] would stop, but after all that training, all that late-night studying, I still had to prove myself.”

Unfortunately, Dr. Duncan’s experience in fellowship is not unique.

A recent survey of hematology and oncology fellows revealed that medical trainees routinely encounter discrimination during their training.

The 17 fellows who were anonymously interviewed in the survey all recalled experiencing or witnessing discriminatory behaviors during their fellowship, mostly from patients. These encounters rarely come to light. Only one respondent officially reported an incident.

The findings, published online November 8 in JAMA Network Open, underscore the need for graduate medical education programs to improve learning environments and support for trainees, lead author Rahma M. Warsame, MD, and colleagues say .
 

Discrimination at work

Initially, Dr. Warsame and co–principal investigator Katharine Price, MD, were tasked with developing strategies to mitigate instances of racism and bias that fellows encountered during training, but both felt it was critical to understand the experiences of their trainees first.

Out of 34 fellows and recent graduates of the hematology and oncology fellowship program of the Mayo Clinic, Rochester, Minn., 20 consented to participate in the study. Of those, 17 were interviewed between July and November 2018. Among the 17 interviewees, six were Asian, two were Black, three were Hispanic, two were multiracial, and four were White.

Dr. Warsame and colleagues found that everyone reported experiencing or witnessing biased or discriminatory events. The majority of these offenses were committed by patients, not faculty or other employees. The researchers largely interpreted most of the incidents as microaggressions.

From the interviews, the researchers identified six central themes. Among them: foreign fellows and U.S.-born trainees being perceived or made to feel like outsiders; inappropriate comments being made toward female employees about their looks, credentials, or marital status; lack of action after reporting incidents or concerns that reporting such incidents would be futile; and strategies fellows used to cope after negative interactions.

One interviewee said, “I was fired by a patient because I have an accent.” Another said that when she is interviewing for jobs, she is always asked if she has children: “Maybe they’re asking in an innocuous manner, but I always feel like people worry. Is this person going to take maternity leave and be less available for work?”

For Dr. Warsame, “the idea that American citizens were frequently made to feel like they do not belong was surprising.”

Not surprising to Dr. Warsame, however, was the importance of fostering diversity and inclusion during fellowship years. Fellows often noted that greater diversity within the program helped create a more inclusive environment.

“[What’s] important to reinforce is the value of creating platforms for honest discussion and intentionally seeking fellows’ voices and perspectives, which in turn makes them feel like they belong,” Dr. Warsame said.

Still, the researchers found that fellows often did not report incidents of discrimination or bias. Only six trainees were aware of policies for reporting patient misconduct or discrimination, and only one ever reported an incident.
 

Where’s the support?

For Dr. Duncan, her encounter 3 years ago with the patient with sunglasses wasn’t her first experience of discrimination on the job — or her last.

Although hurtful in the moment, she had the wherewithal to report the incident to her attending physician, who was equally shocked. Initially unsure of how to handle it, the attending ultimately stepped up and provided “immense support,” Dr. Duncan said

The issue was brought to the attention of the program director, who took swift action. The patient was documented as “disruptive,” informed of that status in writing, and was banned from receiving treatment from trainees at the center, although Dr. Duncan noted he still received the medical care he needed.

Often, however, fellows who report incidents of discrimination and racism receive little support. According to Dr. Warsame and colleagues, most trainees don’t bother reporting these experiences because they believe that doing so would be futile.

“Concerns about reporting included jeopardizing future employability, risk of retaliation, and challenges reporting experiences that could be perceived as subjective and difficult to prove,” the authors write.

For instance, one interviewee said: “I’m afraid to report these things because there’s gonna be repercussions. There’s no way it’s gonna be anonymous.... I just have to toughen up and, you know, get used [to it].”

Dr. Warsame added, “A major challenge for trainees was that they often felt unheard, and at the time, there was no formal debrief regarding discrimination issues when they arose.”

These instances of bias have implications for trainee well-being. In a 2019 study, discrimination that physicians and students experienced during training had adverse effects on their emotional health. Responses from 50 trainees and physicians revealed a wide range of discriminatory experiences, including patients rejecting care and spewing racist, sexist, or homophobic epithets. Many physicians were uncertain about how to respond effectively and appropriately.

Since that study was published and after having completed her own fellowship, Dr. Duncan said she has seen some change for the better.

“There is a lot more awareness around this, and programs are trying to do better in recognizing and responding to incidents,” she said. She noted that it’s important to ensure that those who are directly affected by discriminatory behaviors aren’t left to do all of the “heavy lifting” of addressing and resolving the issues.

The weight of discriminatory incidents, from microaggressions to overt racism, is cumulative and can adversely affect a person’s career. “It’s exhausting -- we need support,” she said.

The Mayo Clinic is working to ensure that trainees receive support. “The study has prompted communication workshops and faculty development to better equip trainees with strategies to address [and report] patients who behave or display disrespectful or discriminatory behavior,” Dr. Warsame said.

She and her colleagues noted that the anonymous hotline used for the survey cultivated a safe environment for candid discussions and that such an approach is “feasible and effective to explore sensitive topics and scalable to various geographic locations and different medical specialties.”

“We recognize that our program must seek this feedback regularly and ensure we keep a finger on the pulse of our trainees,” Dr. Warsame added.

Dr. Warsame and Dr. Duncan have disclosed no relevant financial relationships. Dr. Duncan noted that her views and comments are her own and do not necessarily reflect those of her institution.

A version of this article first appeared on Medscape.com.

A majority of healthy preschoolers were able to recognize emotions shown in static pictures of adults with and without face masks, based on data from a cross-sectional study of 276 children.

Some are concerned about the effects of adults working in preschools wearing face masks on the ability of young children to learn to recognize emotions, study author Juliane Schneider, MD, of University Hospital Lausanne (Switzerland), and colleagues wrote. Previous studies using photographs of faces with digitally added masks have suggested that young children’s emotional recognition was worse with masked faces.

In the study published in JAMA Pediatrics, the researchers tested the impact of masks on the ability of preschool children to identify joy, anger, and sadness. The study included 135 girls and 141 boys aged 36-72 months with a mean age of 52.4 months. The tests were conducted at nine daycare centers.

Children were shown photographs of 15 actors (5 men and 10 women) with and without surgical face masks. The total data set included 90 pictures illustrating joy, anger, and sadness. The children were shown the pictures at random, and they could either name the emotion, point to a card with emoticons showing the three emotions, or respond “I don’t know” or “quit the experiment.” Test sessions lasted approximately 7 minutes per child. Effect sizes were calculated using X² and Cramer V tests.

Overall, 68.8% of the children correctly identified the emotion portrayed; the correct response rate was 70.6% for faces without face masks and 66.9% for those with face masks. Correct recognition of joy was significantly higher for faces without masks than for those with masks (94.8% vs. 87.3), as was correct recognition of sadness (54.1% vs. 48.9%; P < .001 for both). Recognition of anger was not significantly different for unmasked and masked faces (62.2% vs. 64.6%, P = .10).

No significant differences in correct responses appeared between boys and girls and the rate of correct responses increased significantly with age. The rates of “I don’t know,” and “quit the experiment” responses were 3.1% and 2.2%, respectively. In an analysis of incorrect responses, approximately 25% of the children confused anger and sadness, and 21% misidentified joy for images of anger or sadness.

“Overall, participants in this study, who had been exposed to face masks for nearly a year, recognized emotions on pictures better than has been reported in previous research, even with face masks,” the researchers wrote.

The study findings were limited by several factors including the use of static pictures versus real individuals, which limits generalizability, and the lack of data on children with developmental issues, the researchers noted.

Despite relatively small differences and weak effect size (Cramer V scores of 0.2 or less for all), the results show a stronger recognition of emotion, compared with other studies, and highlight the importance of investigating the impact of face masks on other aspects of child development as the COVID-19 pandemic persists, the researchers concluded.

The study received no outside funding. The researchers had no relevant financial conflicts to disclose.

A majority of healthy preschoolers were able to recognize emotions shown in static pictures of adults with and without face masks, based on data from a cross-sectional study of 276 children.

Some are concerned about the effects of adults working in preschools wearing face masks on the ability of young children to learn to recognize emotions, study author Juliane Schneider, MD, of University Hospital Lausanne (Switzerland), and colleagues wrote. Previous studies using photographs of faces with digitally added masks have suggested that young children’s emotional recognition was worse with masked faces.

In the study published in JAMA Pediatrics, the researchers tested the impact of masks on the ability of preschool children to identify joy, anger, and sadness. The study included 135 girls and 141 boys aged 36-72 months with a mean age of 52.4 months. The tests were conducted at nine daycare centers.

Children were shown photographs of 15 actors (5 men and 10 women) with and without surgical face masks. The total data set included 90 pictures illustrating joy, anger, and sadness. The children were shown the pictures at random, and they could either name the emotion, point to a card with emoticons showing the three emotions, or respond “I don’t know” or “quit the experiment.” Test sessions lasted approximately 7 minutes per child. Effect sizes were calculated using X² and Cramer V tests.

Overall, 68.8% of the children correctly identified the emotion portrayed; the correct response rate was 70.6% for faces without face masks and 66.9% for those with face masks. Correct recognition of joy was significantly higher for faces without masks than for those with masks (94.8% vs. 87.3), as was correct recognition of sadness (54.1% vs. 48.9%; P < .001 for both). Recognition of anger was not significantly different for unmasked and masked faces (62.2% vs. 64.6%, P = .10).

No significant differences in correct responses appeared between boys and girls and the rate of correct responses increased significantly with age. The rates of “I don’t know,” and “quit the experiment” responses were 3.1% and 2.2%, respectively. In an analysis of incorrect responses, approximately 25% of the children confused anger and sadness, and 21% misidentified joy for images of anger or sadness.

“Overall, participants in this study, who had been exposed to face masks for nearly a year, recognized emotions on pictures better than has been reported in previous research, even with face masks,” the researchers wrote.

The study findings were limited by several factors including the use of static pictures versus real individuals, which limits generalizability, and the lack of data on children with developmental issues, the researchers noted.

Despite relatively small differences and weak effect size (Cramer V scores of 0.2 or less for all), the results show a stronger recognition of emotion, compared with other studies, and highlight the importance of investigating the impact of face masks on other aspects of child development as the COVID-19 pandemic persists, the researchers concluded.

The study received no outside funding. The researchers had no relevant financial conflicts to disclose.

A majority of healthy preschoolers were able to recognize emotions shown in static pictures of adults with and without face masks, based on data from a cross-sectional study of 276 children.

Some are concerned about the effects of adults working in preschools wearing face masks on the ability of young children to learn to recognize emotions, study author Juliane Schneider, MD, of University Hospital Lausanne (Switzerland), and colleagues wrote. Previous studies using photographs of faces with digitally added masks have suggested that young children’s emotional recognition was worse with masked faces.

In the study published in JAMA Pediatrics, the researchers tested the impact of masks on the ability of preschool children to identify joy, anger, and sadness. The study included 135 girls and 141 boys aged 36-72 months with a mean age of 52.4 months. The tests were conducted at nine daycare centers.

Children were shown photographs of 15 actors (5 men and 10 women) with and without surgical face masks. The total data set included 90 pictures illustrating joy, anger, and sadness. The children were shown the pictures at random, and they could either name the emotion, point to a card with emoticons showing the three emotions, or respond “I don’t know” or “quit the experiment.” Test sessions lasted approximately 7 minutes per child. Effect sizes were calculated using X² and Cramer V tests.

Overall, 68.8% of the children correctly identified the emotion portrayed; the correct response rate was 70.6% for faces without face masks and 66.9% for those with face masks. Correct recognition of joy was significantly higher for faces without masks than for those with masks (94.8% vs. 87.3), as was correct recognition of sadness (54.1% vs. 48.9%; P < .001 for both). Recognition of anger was not significantly different for unmasked and masked faces (62.2% vs. 64.6%, P = .10).

No significant differences in correct responses appeared between boys and girls and the rate of correct responses increased significantly with age. The rates of “I don’t know,” and “quit the experiment” responses were 3.1% and 2.2%, respectively. In an analysis of incorrect responses, approximately 25% of the children confused anger and sadness, and 21% misidentified joy for images of anger or sadness.

“Overall, participants in this study, who had been exposed to face masks for nearly a year, recognized emotions on pictures better than has been reported in previous research, even with face masks,” the researchers wrote.

The study findings were limited by several factors including the use of static pictures versus real individuals, which limits generalizability, and the lack of data on children with developmental issues, the researchers noted.

Despite relatively small differences and weak effect size (Cramer V scores of 0.2 or less for all), the results show a stronger recognition of emotion, compared with other studies, and highlight the importance of investigating the impact of face masks on other aspects of child development as the COVID-19 pandemic persists, the researchers concluded.

The study received no outside funding. The researchers had no relevant financial conflicts to disclose.

People with paroxysmal atrial fibrillation who explored potential triggers of their arrhythmia, and used them to make lifestyle changes, went on to show a 40% decline in subjectively experienced bouts of AFib in a randomized trial with an unusual design.

American Heart Association

But the study didn’t provide evidence that the drop in self-reported AFib necessarily improved their quality of life, its primary endpoint. Nor was there any apparent relationship between potential triggers and AFib episodes detected less subjectively using a handheld electrocardiography monitor.

Although the study – called I-STOP-AFib – has limitations, its results jibe with alcohol intake’s increasingly appreciated status as a potential AFib trigger. It was alone among many possible triggers tested in showing a consistent association with self-reported AFib.

As a result, the study offers no support for such a link between the arrhythmia and caffeine intake, sleep deprivation, dehydration, exercise, or other conditions sometimes perceived as triggers, observed principal investigator Gregory M. Marcus, MD, MAS, University of California, San Francisco, when presenting results at the American Heart Association scientific sessions. He is also lead author on the study’s simultaneous publication in JAMA Cardiology.

The I-STOP-AFib trial was unusual in part for its virtual design, in which participants followed instructions and tracked AFib episodes – both perceived and detected by the handheld ECG device – through a smartphone application. It also featured an N-of-1 randomized comparisons of different weeks in which individuals were or were not exposed to their self-selected trigger.

Such patients following their own weekly personalized randomization were compared to an entirely separate randomized control arm of the trial, in which patients simply tracked any ECG-monitored and self-perceived AFib episodes.
 

Current use in patients

Although wearable and smartphone-based ECG recorders are increasingly popular for AFib screening, Dr. Marcus said the devices may be especially helpful for validating whether a person’s symptoms are actually caused by AFib.

“I have actually suggested to some of my patients that they run some of these experiments,” he said at a media briefing on I-STOP-AFib before his main presentation of the trial. The demonstration might help patients recognize that some perceived triggers actually do not induce AFib.

Allowing patients to determine on their own whether a substance indeed triggers their AFib “is an efficient use of these devices,” Dr. Marcus said. Such N-of-1 exploration of possible triggers “might help free patients up to enjoy substances – caffeine or coffee is one example – that they otherwise might not, and may help actually reassure them that certain exposures –like certain exercises, which can also be beneficial – might actually not be harmful.”

Dr. Marcus and the other authors on the report noted – as he did at the AHA sessions – that the study has several limitations, such as the subjectivity of self-reported AFib, dropouts from the trial that shrank the randomization arms, and a population that may not be very representative.

There is also the potential for detection bias in the group assigned to track their selected triggers, as Dr. Marcus and some observers have noted.

It follows that conscious avoidance of a potential AFib trigger might well lead to a reduction in AFib subjectively identified by symptoms, proposed David Conen, MD, MPH, Population Health Research Institute, McMaster University, Hamilton, Ont. But perhaps there would have been no reduction in AFib had it been objectively documented with the handheld ECG device, he said in an interview.

“If I were to redesign the study,” he said, “I think the primary endpoint should be confirmed atrial fibrillation, because we would have to show first that the specific trigger actually reduced objective AFib events before we then try to address the question whether reducing that trigger improves quality of life.”
 

Unrepresentative sample

The trial entered 446 overwhelmingly White and college-educated adults known to have symptomatic paroxysmal AFib who were “interested in testing a presumed AFib trigger they could readily introduce or withhold” and who owned a smartphone; the average age was 58 years, and 58% were men. The cohort was randomly assigned to the trigger-testing group or the control group, charged only with tracking their AFib.

Of the total, 320, or about 72%, completed the study; those who did not were mostly from the trigger-testing arm, leaving 136 in that group versus 184 patients in the control group.

Potential triggers that participants selected for tracking included, foremost, caffeine, alcohol, reduced sleep, and exercise, followed by lying on the left side, dehydration, large meals, and cold food or drink, the report noted.

Patients in the control group used the smartphone app and handheld ECG monitor (KardiaMobile, AliveCor) to document the duration and severity of AFib episodes daily and received data summary reports through the app weekly for 10 weeks. They then had the option to follow the trigger-testing protocol at least once.

Those in the trigger-testing group conducted their N-of-1 trials by exposing themselves to their chosen potential trigger during 3 separate weeks and avoiding the trigger during 3 other weeks, alternating each of the 6 weeks of trigger exposure or avoidance. They were instructed through the app to start the 6-week sequence with one or the other strategy randomly and to regularly track their AFib.

At the end of 6 weeks, each participant in the trigger-testing group had the opportunity to review their data for any potential trigger-AFib associations. They were then to use the next 4 weeks to enact lifestyle changes based on what they learned – as described in the report and on clinicaltrials.gov. They had the option of repeating the entire N-of-1 sequence at least one more time.

Participants in both the trigger-tracking and control arms were tested at baseline and at 10 weeks using the validated Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire.

AFEQT scores didn’t change significantly over the 10 weeks in either arm, nor were they significantly different in one arm, compared with the other.

On the other hand, patients in the trigger-tracking arm reported significantly fewer daily AFib episodes during the final 4-week period of lifestyle changes based on their N-of-1 trial results, compared to the monitoring-only control group’s final 4 weeks.

The adjusted relative risk in the trigger-tracking arm was 0.60 (95% confidence interval, 0.43-0.83; P < .001), the difference driven by patients who selected alcohol, dehydration, or exercise for their trigger, Dr. Marcus reported.

Only alcohol intake emerged consistently as a significant predictor of risk for self-reported AFib episodes in a series of meta-analyses conducted using all of the individual N-of-1 trials that provided per-protocol data. The odds ratio was 1.77 (95% CI, 1.20-2.69).

I-STOP-AFib explored an important subject “that has been understudied,” Dr. Conen said. “The trial has some limitations that the authors address themselves, but hopefully it opens the path to future studies that can build upon this experience.”

Dr. Marcus reported receiving personal fees and equity interest from InCarda Therapeutics; personal fees from Johnson & Johnson; and grants from Baylis Medical, Medtronic, the National Institutes of Health, the Patient-Centered Outcomes Research Institute, and the California Tobacco-Related Disease Research Program.

A version of this article first appeared on Medscape.com.

People with paroxysmal atrial fibrillation who explored potential triggers of their arrhythmia, and used them to make lifestyle changes, went on to show a 40% decline in subjectively experienced bouts of AFib in a randomized trial with an unusual design.

American Heart Association

But the study didn’t provide evidence that the drop in self-reported AFib necessarily improved their quality of life, its primary endpoint. Nor was there any apparent relationship between potential triggers and AFib episodes detected less subjectively using a handheld electrocardiography monitor.

Although the study – called I-STOP-AFib – has limitations, its results jibe with alcohol intake’s increasingly appreciated status as a potential AFib trigger. It was alone among many possible triggers tested in showing a consistent association with self-reported AFib.

As a result, the study offers no support for such a link between the arrhythmia and caffeine intake, sleep deprivation, dehydration, exercise, or other conditions sometimes perceived as triggers, observed principal investigator Gregory M. Marcus, MD, MAS, University of California, San Francisco, when presenting results at the American Heart Association scientific sessions. He is also lead author on the study’s simultaneous publication in JAMA Cardiology.

The I-STOP-AFib trial was unusual in part for its virtual design, in which participants followed instructions and tracked AFib episodes – both perceived and detected by the handheld ECG device – through a smartphone application. It also featured an N-of-1 randomized comparisons of different weeks in which individuals were or were not exposed to their self-selected trigger.

Such patients following their own weekly personalized randomization were compared to an entirely separate randomized control arm of the trial, in which patients simply tracked any ECG-monitored and self-perceived AFib episodes.
 

Current use in patients

Although wearable and smartphone-based ECG recorders are increasingly popular for AFib screening, Dr. Marcus said the devices may be especially helpful for validating whether a person’s symptoms are actually caused by AFib.

“I have actually suggested to some of my patients that they run some of these experiments,” he said at a media briefing on I-STOP-AFib before his main presentation of the trial. The demonstration might help patients recognize that some perceived triggers actually do not induce AFib.

Allowing patients to determine on their own whether a substance indeed triggers their AFib “is an efficient use of these devices,” Dr. Marcus said. Such N-of-1 exploration of possible triggers “might help free patients up to enjoy substances – caffeine or coffee is one example – that they otherwise might not, and may help actually reassure them that certain exposures –like certain exercises, which can also be beneficial – might actually not be harmful.”

Dr. Marcus and the other authors on the report noted – as he did at the AHA sessions – that the study has several limitations, such as the subjectivity of self-reported AFib, dropouts from the trial that shrank the randomization arms, and a population that may not be very representative.

There is also the potential for detection bias in the group assigned to track their selected triggers, as Dr. Marcus and some observers have noted.

It follows that conscious avoidance of a potential AFib trigger might well lead to a reduction in AFib subjectively identified by symptoms, proposed David Conen, MD, MPH, Population Health Research Institute, McMaster University, Hamilton, Ont. But perhaps there would have been no reduction in AFib had it been objectively documented with the handheld ECG device, he said in an interview.

“If I were to redesign the study,” he said, “I think the primary endpoint should be confirmed atrial fibrillation, because we would have to show first that the specific trigger actually reduced objective AFib events before we then try to address the question whether reducing that trigger improves quality of life.”
 

Unrepresentative sample

The trial entered 446 overwhelmingly White and college-educated adults known to have symptomatic paroxysmal AFib who were “interested in testing a presumed AFib trigger they could readily introduce or withhold” and who owned a smartphone; the average age was 58 years, and 58% were men. The cohort was randomly assigned to the trigger-testing group or the control group, charged only with tracking their AFib.

Of the total, 320, or about 72%, completed the study; those who did not were mostly from the trigger-testing arm, leaving 136 in that group versus 184 patients in the control group.

Potential triggers that participants selected for tracking included, foremost, caffeine, alcohol, reduced sleep, and exercise, followed by lying on the left side, dehydration, large meals, and cold food or drink, the report noted.

Patients in the control group used the smartphone app and handheld ECG monitor (KardiaMobile, AliveCor) to document the duration and severity of AFib episodes daily and received data summary reports through the app weekly for 10 weeks. They then had the option to follow the trigger-testing protocol at least once.

Those in the trigger-testing group conducted their N-of-1 trials by exposing themselves to their chosen potential trigger during 3 separate weeks and avoiding the trigger during 3 other weeks, alternating each of the 6 weeks of trigger exposure or avoidance. They were instructed through the app to start the 6-week sequence with one or the other strategy randomly and to regularly track their AFib.

At the end of 6 weeks, each participant in the trigger-testing group had the opportunity to review their data for any potential trigger-AFib associations. They were then to use the next 4 weeks to enact lifestyle changes based on what they learned – as described in the report and on clinicaltrials.gov. They had the option of repeating the entire N-of-1 sequence at least one more time.

Participants in both the trigger-tracking and control arms were tested at baseline and at 10 weeks using the validated Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire.

AFEQT scores didn’t change significantly over the 10 weeks in either arm, nor were they significantly different in one arm, compared with the other.

On the other hand, patients in the trigger-tracking arm reported significantly fewer daily AFib episodes during the final 4-week period of lifestyle changes based on their N-of-1 trial results, compared to the monitoring-only control group’s final 4 weeks.

The adjusted relative risk in the trigger-tracking arm was 0.60 (95% confidence interval, 0.43-0.83; P < .001), the difference driven by patients who selected alcohol, dehydration, or exercise for their trigger, Dr. Marcus reported.

Only alcohol intake emerged consistently as a significant predictor of risk for self-reported AFib episodes in a series of meta-analyses conducted using all of the individual N-of-1 trials that provided per-protocol data. The odds ratio was 1.77 (95% CI, 1.20-2.69).

I-STOP-AFib explored an important subject “that has been understudied,” Dr. Conen said. “The trial has some limitations that the authors address themselves, but hopefully it opens the path to future studies that can build upon this experience.”

Dr. Marcus reported receiving personal fees and equity interest from InCarda Therapeutics; personal fees from Johnson & Johnson; and grants from Baylis Medical, Medtronic, the National Institutes of Health, the Patient-Centered Outcomes Research Institute, and the California Tobacco-Related Disease Research Program.

A version of this article first appeared on Medscape.com.

People with paroxysmal atrial fibrillation who explored potential triggers of their arrhythmia, and used them to make lifestyle changes, went on to show a 40% decline in subjectively experienced bouts of AFib in a randomized trial with an unusual design.

American Heart Association

But the study didn’t provide evidence that the drop in self-reported AFib necessarily improved their quality of life, its primary endpoint. Nor was there any apparent relationship between potential triggers and AFib episodes detected less subjectively using a handheld electrocardiography monitor.

Although the study – called I-STOP-AFib – has limitations, its results jibe with alcohol intake’s increasingly appreciated status as a potential AFib trigger. It was alone among many possible triggers tested in showing a consistent association with self-reported AFib.

As a result, the study offers no support for such a link between the arrhythmia and caffeine intake, sleep deprivation, dehydration, exercise, or other conditions sometimes perceived as triggers, observed principal investigator Gregory M. Marcus, MD, MAS, University of California, San Francisco, when presenting results at the American Heart Association scientific sessions. He is also lead author on the study’s simultaneous publication in JAMA Cardiology.

The I-STOP-AFib trial was unusual in part for its virtual design, in which participants followed instructions and tracked AFib episodes – both perceived and detected by the handheld ECG device – through a smartphone application. It also featured an N-of-1 randomized comparisons of different weeks in which individuals were or were not exposed to their self-selected trigger.

Such patients following their own weekly personalized randomization were compared to an entirely separate randomized control arm of the trial, in which patients simply tracked any ECG-monitored and self-perceived AFib episodes.
 

Current use in patients

Although wearable and smartphone-based ECG recorders are increasingly popular for AFib screening, Dr. Marcus said the devices may be especially helpful for validating whether a person’s symptoms are actually caused by AFib.

“I have actually suggested to some of my patients that they run some of these experiments,” he said at a media briefing on I-STOP-AFib before his main presentation of the trial. The demonstration might help patients recognize that some perceived triggers actually do not induce AFib.

Allowing patients to determine on their own whether a substance indeed triggers their AFib “is an efficient use of these devices,” Dr. Marcus said. Such N-of-1 exploration of possible triggers “might help free patients up to enjoy substances – caffeine or coffee is one example – that they otherwise might not, and may help actually reassure them that certain exposures –like certain exercises, which can also be beneficial – might actually not be harmful.”

Dr. Marcus and the other authors on the report noted – as he did at the AHA sessions – that the study has several limitations, such as the subjectivity of self-reported AFib, dropouts from the trial that shrank the randomization arms, and a population that may not be very representative.

There is also the potential for detection bias in the group assigned to track their selected triggers, as Dr. Marcus and some observers have noted.

It follows that conscious avoidance of a potential AFib trigger might well lead to a reduction in AFib subjectively identified by symptoms, proposed David Conen, MD, MPH, Population Health Research Institute, McMaster University, Hamilton, Ont. But perhaps there would have been no reduction in AFib had it been objectively documented with the handheld ECG device, he said in an interview.

“If I were to redesign the study,” he said, “I think the primary endpoint should be confirmed atrial fibrillation, because we would have to show first that the specific trigger actually reduced objective AFib events before we then try to address the question whether reducing that trigger improves quality of life.”
 

Unrepresentative sample

The trial entered 446 overwhelmingly White and college-educated adults known to have symptomatic paroxysmal AFib who were “interested in testing a presumed AFib trigger they could readily introduce or withhold” and who owned a smartphone; the average age was 58 years, and 58% were men. The cohort was randomly assigned to the trigger-testing group or the control group, charged only with tracking their AFib.

Of the total, 320, or about 72%, completed the study; those who did not were mostly from the trigger-testing arm, leaving 136 in that group versus 184 patients in the control group.

Potential triggers that participants selected for tracking included, foremost, caffeine, alcohol, reduced sleep, and exercise, followed by lying on the left side, dehydration, large meals, and cold food or drink, the report noted.

Patients in the control group used the smartphone app and handheld ECG monitor (KardiaMobile, AliveCor) to document the duration and severity of AFib episodes daily and received data summary reports through the app weekly for 10 weeks. They then had the option to follow the trigger-testing protocol at least once.

Those in the trigger-testing group conducted their N-of-1 trials by exposing themselves to their chosen potential trigger during 3 separate weeks and avoiding the trigger during 3 other weeks, alternating each of the 6 weeks of trigger exposure or avoidance. They were instructed through the app to start the 6-week sequence with one or the other strategy randomly and to regularly track their AFib.

At the end of 6 weeks, each participant in the trigger-testing group had the opportunity to review their data for any potential trigger-AFib associations. They were then to use the next 4 weeks to enact lifestyle changes based on what they learned – as described in the report and on clinicaltrials.gov. They had the option of repeating the entire N-of-1 sequence at least one more time.

Participants in both the trigger-tracking and control arms were tested at baseline and at 10 weeks using the validated Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire.

AFEQT scores didn’t change significantly over the 10 weeks in either arm, nor were they significantly different in one arm, compared with the other.

On the other hand, patients in the trigger-tracking arm reported significantly fewer daily AFib episodes during the final 4-week period of lifestyle changes based on their N-of-1 trial results, compared to the monitoring-only control group’s final 4 weeks.

The adjusted relative risk in the trigger-tracking arm was 0.60 (95% confidence interval, 0.43-0.83; P < .001), the difference driven by patients who selected alcohol, dehydration, or exercise for their trigger, Dr. Marcus reported.

Only alcohol intake emerged consistently as a significant predictor of risk for self-reported AFib episodes in a series of meta-analyses conducted using all of the individual N-of-1 trials that provided per-protocol data. The odds ratio was 1.77 (95% CI, 1.20-2.69).

I-STOP-AFib explored an important subject “that has been understudied,” Dr. Conen said. “The trial has some limitations that the authors address themselves, but hopefully it opens the path to future studies that can build upon this experience.”

Dr. Marcus reported receiving personal fees and equity interest from InCarda Therapeutics; personal fees from Johnson & Johnson; and grants from Baylis Medical, Medtronic, the National Institutes of Health, the Patient-Centered Outcomes Research Institute, and the California Tobacco-Related Disease Research Program.

A version of this article first appeared on Medscape.com.

On Nov. 12, president Joe Biden said he will nominate Robert Califf, MD, to be commissioner of the U.S. Food and Drug Administration, the top U.S. regulator of drugs and medical devices.

Dr. Califf, a cardiologist, served as FDA chief in the Obama administration, leading the agency from Feb. 2016 to Jan. 2017.

The coming nomination ends nearly 11 months of speculation over Mr. Biden’s pick to the lead the agency during the ongoing pandemic. Janet Woodcock, MD, an FDA veteran, has been serving as acting commissioner. The White House faced a Tuesday deadline to make a nomination or see Dr. Woodcock’s tenure as acting chief expire under federal law.

The initial reaction to the idea of Dr. Califf’s return to the FDA drew mixed reactions.

The nonprofit watchdog Public Citizen issued a statement about its opposition to the potential nomination of Dr. Califf. Michael Carome, MD, director of Public Citizen’s Health Research Group, said the United States “desperately needs an FDA leader who will reverse the decades-long trend in which the agency’s relationship with the pharmaceutical and medical-device industries has grown dangerously cozier – resulting in regulatory capture of the agency by industry.”

But the idea of Dr. Califf returning to the FDA pleased Harlan Krumholz, MD, a cardiologist who has been a leader in outcomes research.

Dr. Krumholz tweeted that the Biden administration likely was testing the reaction to a possible Dr. Califf nomination before making it official. “I realize that this is being floated and not officially announced ... but the nomination of [Califf] just makes so much sense,” Dr. Krumholz tweeted. Dr. Califf’s “expertise as a researcher, policymaker, clinician are unparalleled. In a time of partisanship, he should be a slam-dunk confirmation.”

Dr. Califf’s 2016 Senate confirmation process was marked by dissent from several Democrats who questioned his ties to industry. But the chamber voted 89-4 to confirm him.

A version of this article first appeared on Medscape.com.

On Nov. 12, president Joe Biden said he will nominate Robert Califf, MD, to be commissioner of the U.S. Food and Drug Administration, the top U.S. regulator of drugs and medical devices.

Dr. Califf, a cardiologist, served as FDA chief in the Obama administration, leading the agency from Feb. 2016 to Jan. 2017.

The coming nomination ends nearly 11 months of speculation over Mr. Biden’s pick to the lead the agency during the ongoing pandemic. Janet Woodcock, MD, an FDA veteran, has been serving as acting commissioner. The White House faced a Tuesday deadline to make a nomination or see Dr. Woodcock’s tenure as acting chief expire under federal law.

The initial reaction to the idea of Dr. Califf’s return to the FDA drew mixed reactions.

The nonprofit watchdog Public Citizen issued a statement about its opposition to the potential nomination of Dr. Califf. Michael Carome, MD, director of Public Citizen’s Health Research Group, said the United States “desperately needs an FDA leader who will reverse the decades-long trend in which the agency’s relationship with the pharmaceutical and medical-device industries has grown dangerously cozier – resulting in regulatory capture of the agency by industry.”

But the idea of Dr. Califf returning to the FDA pleased Harlan Krumholz, MD, a cardiologist who has been a leader in outcomes research.

Dr. Krumholz tweeted that the Biden administration likely was testing the reaction to a possible Dr. Califf nomination before making it official. “I realize that this is being floated and not officially announced ... but the nomination of [Califf] just makes so much sense,” Dr. Krumholz tweeted. Dr. Califf’s “expertise as a researcher, policymaker, clinician are unparalleled. In a time of partisanship, he should be a slam-dunk confirmation.”

Dr. Califf’s 2016 Senate confirmation process was marked by dissent from several Democrats who questioned his ties to industry. But the chamber voted 89-4 to confirm him.

A version of this article first appeared on Medscape.com.

On Nov. 12, president Joe Biden said he will nominate Robert Califf, MD, to be commissioner of the U.S. Food and Drug Administration, the top U.S. regulator of drugs and medical devices.

Dr. Califf, a cardiologist, served as FDA chief in the Obama administration, leading the agency from Feb. 2016 to Jan. 2017.

The coming nomination ends nearly 11 months of speculation over Mr. Biden’s pick to the lead the agency during the ongoing pandemic. Janet Woodcock, MD, an FDA veteran, has been serving as acting commissioner. The White House faced a Tuesday deadline to make a nomination or see Dr. Woodcock’s tenure as acting chief expire under federal law.

The initial reaction to the idea of Dr. Califf’s return to the FDA drew mixed reactions.

The nonprofit watchdog Public Citizen issued a statement about its opposition to the potential nomination of Dr. Califf. Michael Carome, MD, director of Public Citizen’s Health Research Group, said the United States “desperately needs an FDA leader who will reverse the decades-long trend in which the agency’s relationship with the pharmaceutical and medical-device industries has grown dangerously cozier – resulting in regulatory capture of the agency by industry.”

But the idea of Dr. Califf returning to the FDA pleased Harlan Krumholz, MD, a cardiologist who has been a leader in outcomes research.

Dr. Krumholz tweeted that the Biden administration likely was testing the reaction to a possible Dr. Califf nomination before making it official. “I realize that this is being floated and not officially announced ... but the nomination of [Califf] just makes so much sense,” Dr. Krumholz tweeted. Dr. Califf’s “expertise as a researcher, policymaker, clinician are unparalleled. In a time of partisanship, he should be a slam-dunk confirmation.”

Dr. Califf’s 2016 Senate confirmation process was marked by dissent from several Democrats who questioned his ties to industry. But the chamber voted 89-4 to confirm him.

A version of this article first appeared on Medscape.com.

Venetoclax’s regulatory approvals, its success as monotherapy for chronic lymphocytic leukemia (CLL) and other lymphoid neoplasms, and its activity in combination against acute myeloid leukemia (AML) have helped pave the way for BCL2 and MCL1 inhibitors that target prosurvival, antiapoptosis proteins.

A first-in-class specific inhibitor of BCL2, venetoclax has been quickly followed by drugs that target either BCL2 or proteins with similar prosurvival function, especially MCL1. A review by Andrew W. Roberts, MD, of the Walter and Eliza Hall Institute of Medical Research, Melbourne, and associates details their key features, including their activity and tolerability and resistance issues. The review was published in Blood .
 

BH3 mimetics

BH3 mimetics, a new class of small-molecule anticancer drugs, enable specific targeting of BCL2 and MCL1, commonly expressed antiapoptotic proteins in hematologic cancers. The BH3 mimetics inhibit prosurvival BCL2 proteins, enabling activation of the apoptosis effectors BAX and BK that make the outer mitochondrial membranes permeable. This result triggers apoptosis in many cells, while sensitizing others to cell death when the BH3 mimetics are combined with other antineoplastic drugs. The BAX/BAK–driven effect on mitochondrial membranes is to undermine normal energy production, allowing leakage of cell contents, including cytochrome c, a trigger of proteolytic enzymes and cellular demolition.

Navitoclax was the first potent BCL2 inhibitor to enter clinical trials. While it demonstrated moderate single-agent activity in relapsed CLL and indolent B-cell lymphomas, its dose-limiting toxicity of thrombocytopenia precluded further exploration of BCL2 inhibition. Navitoclax is being developed for hematologic disease (for example, myelofibrosis and acute lymphoblastic leukemia). Clinical development of other BH3 mimetics is only in the earliest stages, the authors wrote.

Venetoclax, to avoid this on-target thrombocytopenia, was designed to specifically inhibit BCL2 with great selectivity, a feature not found in naturally occurring BH3-only proteins. The fact that it could inhibit a single prosurvival protein and have important clinical activity proved enormously stimulating to development of this drug class. Potent BH3 mimetics now can also selectively target MCL1, which plays a central role in plasma cells (mature B lymphocytes are highly reliant on BCL2).

In CLL, dependence on BCL2 is high. Venetoclax, since it was first approved by the Food and Drug Administration in April 2016 as monotherapy for relapsed/refractory del(17p) CLL, has been approved widely in combination with rituximab in relapsed/refractory CLL and for unfit patients with newly diagnosed CLL in combination with obinutuzumab. With venetoclax monotherapy, quickly achieved high objective response rates (79%) and complete remissions (20%) revealed the drug’s dose-limiting toxicity of tumor lysis syndrome (TLS). This necessitated gradual ramp-up dosing in those with high disease burden or reduced renal function. Also, despite the adoption of a venetoclax/rituximab combination as standard for relapsed/refractory CLL, the authors underscored that evidence for an additive rituximab benefit is modest and limited.
 

Resistance

While resistance to venetoclax leading to treatment failure is uncommon in the first year, secondary resistance occurs through several independently occurring mechanisms, including mutations in BCL2 (for example, Gly101Val), overexpression of MCL1, and overexpression of BCLxL. Usual venetoclax therapy is now time limited. Early data on re-exposure shows high rates (about 70%) of secondary responses.

AML

In AML, a more heterogeneous disease than CLL, BCL2 expression varies widely and can be heterogeneous even within a single patient’s leukemic cell population. While responses to venetoclax monotherapy were not durable, combination therapy with azacitidine has revealed enhanced activity. The venetoclax/azacitidine combination has been widely adopted as first-line therapy for older and unfit AML patients. Myelosuppression is the major toxicity.

“As venetoclax is the first in a new class of anticancer drug,” Andrew W. Roberts, MD, said in an interview, “we are still in the process of working out how it can be best utilized. Regimens free of DNA-damaging chemotherapy using this BCL2 inhibitor in combination with obinutuzumab or rituximab in CLL are established. Across B-cell neoplasia (e.g. CLL, mantle cell lymphoma, follicular lymphoma), the challenge is to work out whether venetoclax can enhance other ‘chemotherapy-free’ regimens.” He continued: “In contrast, for AML, learning how venetoclax can be safely combined with intensive chemotherapy is a priority, as we seek to improve outcomes for patients with poor prognosis disease. For MCL1 inhibitors, there is excitement about their potential, but their clinical development remains in its infancy.”

The authors reported multiple financial disclosures.

Venetoclax’s regulatory approvals, its success as monotherapy for chronic lymphocytic leukemia (CLL) and other lymphoid neoplasms, and its activity in combination against acute myeloid leukemia (AML) have helped pave the way for BCL2 and MCL1 inhibitors that target prosurvival, antiapoptosis proteins.

A first-in-class specific inhibitor of BCL2, venetoclax has been quickly followed by drugs that target either BCL2 or proteins with similar prosurvival function, especially MCL1. A review by Andrew W. Roberts, MD, of the Walter and Eliza Hall Institute of Medical Research, Melbourne, and associates details their key features, including their activity and tolerability and resistance issues. The review was published in Blood .
 

BH3 mimetics

BH3 mimetics, a new class of small-molecule anticancer drugs, enable specific targeting of BCL2 and MCL1, commonly expressed antiapoptotic proteins in hematologic cancers. The BH3 mimetics inhibit prosurvival BCL2 proteins, enabling activation of the apoptosis effectors BAX and BK that make the outer mitochondrial membranes permeable. This result triggers apoptosis in many cells, while sensitizing others to cell death when the BH3 mimetics are combined with other antineoplastic drugs. The BAX/BAK–driven effect on mitochondrial membranes is to undermine normal energy production, allowing leakage of cell contents, including cytochrome c, a trigger of proteolytic enzymes and cellular demolition.

Navitoclax was the first potent BCL2 inhibitor to enter clinical trials. While it demonstrated moderate single-agent activity in relapsed CLL and indolent B-cell lymphomas, its dose-limiting toxicity of thrombocytopenia precluded further exploration of BCL2 inhibition. Navitoclax is being developed for hematologic disease (for example, myelofibrosis and acute lymphoblastic leukemia). Clinical development of other BH3 mimetics is only in the earliest stages, the authors wrote.

Venetoclax, to avoid this on-target thrombocytopenia, was designed to specifically inhibit BCL2 with great selectivity, a feature not found in naturally occurring BH3-only proteins. The fact that it could inhibit a single prosurvival protein and have important clinical activity proved enormously stimulating to development of this drug class. Potent BH3 mimetics now can also selectively target MCL1, which plays a central role in plasma cells (mature B lymphocytes are highly reliant on BCL2).

In CLL, dependence on BCL2 is high. Venetoclax, since it was first approved by the Food and Drug Administration in April 2016 as monotherapy for relapsed/refractory del(17p) CLL, has been approved widely in combination with rituximab in relapsed/refractory CLL and for unfit patients with newly diagnosed CLL in combination with obinutuzumab. With venetoclax monotherapy, quickly achieved high objective response rates (79%) and complete remissions (20%) revealed the drug’s dose-limiting toxicity of tumor lysis syndrome (TLS). This necessitated gradual ramp-up dosing in those with high disease burden or reduced renal function. Also, despite the adoption of a venetoclax/rituximab combination as standard for relapsed/refractory CLL, the authors underscored that evidence for an additive rituximab benefit is modest and limited.
 

Resistance

While resistance to venetoclax leading to treatment failure is uncommon in the first year, secondary resistance occurs through several independently occurring mechanisms, including mutations in BCL2 (for example, Gly101Val), overexpression of MCL1, and overexpression of BCLxL. Usual venetoclax therapy is now time limited. Early data on re-exposure shows high rates (about 70%) of secondary responses.

AML

In AML, a more heterogeneous disease than CLL, BCL2 expression varies widely and can be heterogeneous even within a single patient’s leukemic cell population. While responses to venetoclax monotherapy were not durable, combination therapy with azacitidine has revealed enhanced activity. The venetoclax/azacitidine combination has been widely adopted as first-line therapy for older and unfit AML patients. Myelosuppression is the major toxicity.

“As venetoclax is the first in a new class of anticancer drug,” Andrew W. Roberts, MD, said in an interview, “we are still in the process of working out how it can be best utilized. Regimens free of DNA-damaging chemotherapy using this BCL2 inhibitor in combination with obinutuzumab or rituximab in CLL are established. Across B-cell neoplasia (e.g. CLL, mantle cell lymphoma, follicular lymphoma), the challenge is to work out whether venetoclax can enhance other ‘chemotherapy-free’ regimens.” He continued: “In contrast, for AML, learning how venetoclax can be safely combined with intensive chemotherapy is a priority, as we seek to improve outcomes for patients with poor prognosis disease. For MCL1 inhibitors, there is excitement about their potential, but their clinical development remains in its infancy.”

The authors reported multiple financial disclosures.

Venetoclax’s regulatory approvals, its success as monotherapy for chronic lymphocytic leukemia (CLL) and other lymphoid neoplasms, and its activity in combination against acute myeloid leukemia (AML) have helped pave the way for BCL2 and MCL1 inhibitors that target prosurvival, antiapoptosis proteins.

A first-in-class specific inhibitor of BCL2, venetoclax has been quickly followed by drugs that target either BCL2 or proteins with similar prosurvival function, especially MCL1. A review by Andrew W. Roberts, MD, of the Walter and Eliza Hall Institute of Medical Research, Melbourne, and associates details their key features, including their activity and tolerability and resistance issues. The review was published in Blood .
 

BH3 mimetics

BH3 mimetics, a new class of small-molecule anticancer drugs, enable specific targeting of BCL2 and MCL1, commonly expressed antiapoptotic proteins in hematologic cancers. The BH3 mimetics inhibit prosurvival BCL2 proteins, enabling activation of the apoptosis effectors BAX and BK that make the outer mitochondrial membranes permeable. This result triggers apoptosis in many cells, while sensitizing others to cell death when the BH3 mimetics are combined with other antineoplastic drugs. The BAX/BAK–driven effect on mitochondrial membranes is to undermine normal energy production, allowing leakage of cell contents, including cytochrome c, a trigger of proteolytic enzymes and cellular demolition.

Navitoclax was the first potent BCL2 inhibitor to enter clinical trials. While it demonstrated moderate single-agent activity in relapsed CLL and indolent B-cell lymphomas, its dose-limiting toxicity of thrombocytopenia precluded further exploration of BCL2 inhibition. Navitoclax is being developed for hematologic disease (for example, myelofibrosis and acute lymphoblastic leukemia). Clinical development of other BH3 mimetics is only in the earliest stages, the authors wrote.

Venetoclax, to avoid this on-target thrombocytopenia, was designed to specifically inhibit BCL2 with great selectivity, a feature not found in naturally occurring BH3-only proteins. The fact that it could inhibit a single prosurvival protein and have important clinical activity proved enormously stimulating to development of this drug class. Potent BH3 mimetics now can also selectively target MCL1, which plays a central role in plasma cells (mature B lymphocytes are highly reliant on BCL2).

In CLL, dependence on BCL2 is high. Venetoclax, since it was first approved by the Food and Drug Administration in April 2016 as monotherapy for relapsed/refractory del(17p) CLL, has been approved widely in combination with rituximab in relapsed/refractory CLL and for unfit patients with newly diagnosed CLL in combination with obinutuzumab. With venetoclax monotherapy, quickly achieved high objective response rates (79%) and complete remissions (20%) revealed the drug’s dose-limiting toxicity of tumor lysis syndrome (TLS). This necessitated gradual ramp-up dosing in those with high disease burden or reduced renal function. Also, despite the adoption of a venetoclax/rituximab combination as standard for relapsed/refractory CLL, the authors underscored that evidence for an additive rituximab benefit is modest and limited.
 

Resistance

While resistance to venetoclax leading to treatment failure is uncommon in the first year, secondary resistance occurs through several independently occurring mechanisms, including mutations in BCL2 (for example, Gly101Val), overexpression of MCL1, and overexpression of BCLxL. Usual venetoclax therapy is now time limited. Early data on re-exposure shows high rates (about 70%) of secondary responses.

AML

In AML, a more heterogeneous disease than CLL, BCL2 expression varies widely and can be heterogeneous even within a single patient’s leukemic cell population. While responses to venetoclax monotherapy were not durable, combination therapy with azacitidine has revealed enhanced activity. The venetoclax/azacitidine combination has been widely adopted as first-line therapy for older and unfit AML patients. Myelosuppression is the major toxicity.

“As venetoclax is the first in a new class of anticancer drug,” Andrew W. Roberts, MD, said in an interview, “we are still in the process of working out how it can be best utilized. Regimens free of DNA-damaging chemotherapy using this BCL2 inhibitor in combination with obinutuzumab or rituximab in CLL are established. Across B-cell neoplasia (e.g. CLL, mantle cell lymphoma, follicular lymphoma), the challenge is to work out whether venetoclax can enhance other ‘chemotherapy-free’ regimens.” He continued: “In contrast, for AML, learning how venetoclax can be safely combined with intensive chemotherapy is a priority, as we seek to improve outcomes for patients with poor prognosis disease. For MCL1 inhibitors, there is excitement about their potential, but their clinical development remains in its infancy.”

The authors reported multiple financial disclosures.